MULTIVALENT AGONISTS, PARTIAL AGONISTS AND ANTAGONISTS OF THE GABA RECEPTORS

Abstract: Disclosed are multibinding compounds which are agonists, partial agonists, inverse agonists, partial inverse agonist or antagonists of the GABA receptors, which are involved in neurological disorders. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is an agonist, partial agonist, inverse agonist, partial inverse agonist or antagonist of the GABA receptors. The multibinding compounds of this invention are useful in the treatment of neurological disorders such as anxiety, depression, sleep and seizure disorders, emesis and overdoses of benzodiazepine-type drugs, and producing sedation, hypnosis, retrograde amnesia, and enhancing alertness and the like.

Description: MULTIVALENT AGONISTS, PARTIAL AGONISTS AND ANTAGONISTS OF THE GABA RECEPTORS BACKGROUND OF THE INVENTION Field of the Invention This invention relates to novel compounds which selectively bind to GABA receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating anxiety, panic disorders, depression, sleep and seizure disorders, overdoses of benzodiazepine-type drugs, and emesis, for producing sedation, hypnosis, retrograde amnesia and enhancing alertness and memory. State of the Art A large number of patients suffer from anxiety and related disorders. These disorders include panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorders not otherwise specified. Anxiety disorders are generally treated with counseling and/or drugs. In the central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between neurotransmitters released by a sending neuron and surface receptors on receiving neurons. This interaction causes excitation of the receiving neuron. Research efforts have focused on developing compounds which interact with the various receptors in the central nervous system to treat or prevent anxiety and related disorders. γ-Aminobutyric acid (GABA) is a major inhibitory amino acid transmitter in the mammalian brain. (Roberts & Frankel, J. Biol. Chem. 187: 55-63, 1950; Udenfriend, J. Biol. Chem. : 187: 65-69, 1950). GABA has been implicated in the etiology of seizure disorders, sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience, 8: 21 -44. 1985). GABA, which is widely, although unequally, distributed through the mammalian brain, is a transmitter at approximately 30% of the synapses in the brain. In most regions of the brain, GABA is associated with local inhibitory neurons and only in two regions, GABA is associated with longer projections. GABA mediates many of its actions through a complex of proteins localized both on cell bodies and nerve endings; these are the GABA A receptors. Postsynaptic responses to GABA are mediated through alterations in chloride conductance that generally, although not invariably, lead to hyperpolarization of the cell. The complex of proteins associated with postsynaptic GABA responses is a major site of action for a number of structurally unrelated compounds capable of modifying postsynaptic responses to GABA. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (either sedative, anxiolytic, and anticonvulsant, or wakefulness, seizures, and anxiety). 1,4-Benzodiazepines are widely used to treat anxiety and related disorders. Examples of benzodiazepines include chlordiazepoxide, diazepam, flurazepam, and triazolam. These compounds are used as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A major action of benzodiazepines is enhancement of GABAergic inhibition. The benzodiazepines enhance presynaptic inhibition of a monosynaptic ventral root reflex, a GABA-mediated event (Schmidt et al., Arch. Rxp. Path. Pharmakol. 258: 69-82 (1967)); Tallman et al, Science, 207: 274-81 (1980), Haefley et al, Handb. F.xptl. Pharmacol. 33: 95-102 (1981)). As the nature of the interaction between GABA and the benzodiazepines has become understood, it appears that the behaviorally important interactions of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems Each modified system, in turn, may be associated with the expression of a behavior GABA and related analogs can interact with low affinity (1 mM) at the GABA binding site to enhance the binding of benzodiazepines to the clonazepam-sensitive site (Tallman et al , Nature, 274 383-85 (1978)) This enhancement is caused by an increase in the affinity of the benzodiazepine binding site due to occupancy of the GABA site Both GABA and benzodiazepine sites aie allostencally linked in the membrane as part of a complex of proteins For a number of GABA analogs, the ability to enhance diazepam binding by 50% of maximum and the ability to inhibit the binding of GABA to brain membranes by 50% can be directly correlated For example, enhancement of benzodiazepine binding by GABA agonists is blocked by the GABA receptor antagonist (-r) bicucullme (Tallman et al , Nature, 274 383-85 (1978)) There are multiple "isoreceptor" or allehc forms of the GABA receptor (Tallman & Gallagei, Ann. Rev . Neurosci. 8. 21-44 (1985)) Isoreceptors are believed to be important m the etiology of psychiatric disorders The GABA^ receptor subunits have been cloned from bovine and human cDNA libraries A number of distinct cDNAs have been identified as subunits of the GABA receptor complex by cloning and expression These are categorized into α, β, δ and e, and provide a molecular basis for the GABA X receptor heterogeneity and distinctive regional pharmacology The γ -sub unit appears to enable drugs like benzodiazepines to modify the GABA responses The presence of low Hill coefficients m the binding of ligands to the GABA X receptor indicates unique profiles of subtype specific pharmacological action Drugs that interact at the GABA A receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of GABA. For example, the beta-carbolines were first isolated based upon their ability to inhibit competitively the binding of diazepam to its binding site (Nielsen et al, Life Sci., 25: 679-86 (1979)). The receptor binding assay is not totally predictive about the biological activity of such compounds; agonists, partial agonists, inverse agonists, and antagonists can inhibit binding. For example, compounds such as beta-carbolines and analogs thereof can antagonize the actions of diazepam behaviorally (Tenen & Hirsch, Nature, 288: 609-10 (1980)). Beta-carbolines possess intrinsic activity of their own opposite to that of the benzodiazepines, and are therefore known as inverse agonists. A number of compounds, such as imidazodiazepme (Hunkeler et al., Nature, 290: 514-516 (1981)), are specific antagonists of the benzodiazepine receptor, and are able to inhibit the binding of benzodiazepines. Imidazodiazepine is a high affinity competitive inhibitor of benzodiazepine and beta-carboline binding and can block the pharmacological actions of both these classes of compounds. By itself, it possesses little intrinsic pharmacological activity in animals and humans (Hunkeler et al, Nature, 290: 514-16 (1981); Darragh et al., Eur. J. Clin. Pharmacol. 14: 569-70 (1983)). This compound is the ligand of choice for binding to GABA A receptors because it does not possess receptor subtype specificity and measures each state of the receptor. Compounds possessing activity similar to the benzodiazepines are called agonists. Compounds possessing activity opposite to benzodiazepines are called inverse agonists, and the compounds blocking both types of activity have been termed antagonists. This categorization has been developed to emphasize the fact that a wide variety of compounds can produce a spectrum of pharmacological effects, to indicate that compounds can interact at the same receptor to produce opposite effects, and to indicate that beta-carbolines and antagonists with intrinsic anxiogenic effects are not synonymous. A biochemical test for the pharmacological and behavioral properties of compounds that interact with the benzodiazepine receptor continues to emphasize the interaction with the GABAergic system. In contrast to the benzodiazepines, which show an increase in their affinity due to GABA (Tallman et al, Nature, 274: 383-85 (1978), Tallman et al., Science, 207: 274-81 (1980)), compounds with antagonist properties show little GABA shift (i.e., change in receptor affinity due to GABA) (Mohler & Richards Nature, 294: 763-65 (1981)), and the inverse agonists actually show a decrease in affinity due to GABA (Braestrup & Nielson Nature, 294: 472-474 (1981)). Thus, the GABA shift predicts generally the expected behavioral properties of the compounds. It would be advantageous to develop new compounds for interacting with the GABA receptors. The present invention provides such compounds. Advantages include increased potency, increased selectivity for GAB A A stotpes, controlled efficience, i.e., partial agonist. SUMMARY OF THE INVENTION This invention is directed to novel multibinding compounds (agents) that are agonists, partial agonists, inverse agonists and antagonists of the GABA receptors. The multibinding compounds of this invention are useful in the treatment and prevention of disorders mediated by the GABA receptors, for example, treating and preventing anxiety, depression, sleep and seizure disorders, overdoses of benzodiazepine-type drugs, and emesis, and enhancing alertness and memory. Accordingly, in one of its composition aspects, this invention provides a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises an agonist, partial agonist, inverse agonist and antagonist of the GABA receptors, and pharmaceutically-acceptable salts thereof. In another of its composition aspects, this invention provides a multibinding compound of formula I: (L) p (X) q I wherein each L is independently a ligand which binds to a GABA receptor; each X is independently a linker; p is an integer of from 2 to 10; and q is an integer of from 1 to 20; and pharmaceutically-acceptable salts thereof. Preferably, q is less than/? in the multibinding compounds of this invention. Preferably, each ligand, L, in the multibinding compound of formula I is independently selected from a compound of formula A-F. B where Z a ; may be an atom or group of atoms serving to connect the ligand, L, to the linker, X; and wherein R,_ 4 and R„ may be, independently, H, alkyl, substituted alkyl, aryl, or cycloalkyl, preferably lower alkyl, more preferably, methyl or ethyl; R 5.6 may be, independently, H, alkyl, substituted alkyl, aryl, preferably lower alkyl, more preferably methyl, or halo, preferably chloro; R 8 , R g ,, R 2 , and R 2 ,. may be, independently, H, halo, substituted alkyl, aryl, preferably F, Cl or Br, or nitro; In still another of its composition aspects, this invention provides a multibinding compound of formula II: L'- X'- L' II wherein each L' is independently a ligand which is an agonist, partial agonist, inverse agonist or antagonist of the GABA receptors and X' is a linker; and pharmaceutically-acceptable salts thereof. Examples of compounds of this formula are shown below: A-Zj 2,-A A-Z -Q-Z b -B A-Zr-Q-Z f -F C-Zj ■ Zf-F B-Z„- Z b -B C-Z c —@—Z d -D B-Z b -Q—Zc-C D-Z • ZrE C-Zj Z c -C E-Z,—Q—Z f -F B-Ztf-Q—Z d -D D-Z,, • 2,-F D-Z d ■ Z_-D A-ZΓ-^—Z--.C B-Z b -^-z E F-Zf Z f -F A-ZΓ-^-Z- Γ E C-Z-^-ZΓE Also included In this Invention are ligands, L, derived from 4-am_nobutanoic acid and represented by the symbol, ZgG. Three respresentatlve examples are given and are represented by the generic structures below. A-Z- ■-0 c-Z c - Zg-G E--H Preferably, in the multibinding compound of Formula II, each ligand, L', is preferably independently selected from the group consisting of Formula A-F; and X" is a linker; and pharmaceutically-acceptable salts thereof. Preferably, in the above embodiments, each linker (i.e., X, X' or X") independently has the formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(S), -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene. alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR'-, -C(=NR')-NR'-, -NR'-C(=NR')-, -NR'-C(O)-O-, -N=C(X a )-NR'-, -P(O)(OR')-O-, -S(O) π CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. In yet another of its composition aspects, this invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises an agonist, partial agonist, inverse agonist or antagonist of the GABA receptors; and pharmaceutically-acceptable salts thereof. This invention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound derived from ligands of Formula A-F. The multibinding compounds of this invention are effective agonists, partial agonists or antagonists of the GABA receptors, which are involved in a number of neurological disorders. Accordingly, in one of its method aspects, this invention provides a method for treating various neurological disorders mediated by GABA receptors in a patient, the method comprising administering to a patient having a neurological disorder a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises an agonist, partial agonist or antagonist of the GABA receptors; and pharmaceutically-acceptable salts thereof. This invention is also directed to general synthetic methods for generating large libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties with respect to the GABA receptors. The diverse multimeric compound libraries provided by this invention are synthesized by combining a linker or linkers with a ligand or ligands to provide for a library of multimeric compounds wherein the linker and ligand each have complementary functional groups permitting covalent linkage. The library of linkers is preferably selected to have diverse properties such as valency, linker length, linker geometry and rigidity, hydrophilicity or hydrophobicity, amphiphilicity, acidity, basicity and polarability and /or polarization. The library of ligands is preferably selected to have diverse attachment points on the same ligand, different functional groups at the same site of otherwise the same ligand, and the like. This invention is also directed to general synthetic methods for generating large libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties with respect to the GABA receptors. The diverse multimeric compound libraries provided by this invention are synthesized by combining a linker or linkers with a ligand or ligands to provide for a library of multimeric compounds wherein the linker and ligand each have complementary functional groups permitting covalent linkage. The library of linkers is preferably selected to have diverse properties such as valency, linker length, linker geometry and rigidity, hydrophilicity or hydrophobicity, amphiphilicity, acidity, basicity and polarability and /or polarization. The library of ligands is preferably selected to have diverse attachment points on the same ligand, different functional groups at the same site of otherwise the same ligand, and the like. This invention is also directed to libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties with respect to the GABA receptors. These libraries are prepared via the methods described above and permit the rapid and efficient evaluation of what molecular constraints impart multibinding properties to a ligand or a class of ligands targeting the GABA receptors. Accordingly, in one of its method aspects, this invention is directed to a method for identifying multimeric ligand compounds possessing multibinding properties with respect to the GABA receptors which method comprises: (a) identifying a ligand or a mixture of ligands which bind to the GABA receptors wherein each ligand contains at least one reactive functionality; (b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and (d) assaying the multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds possessing multibinding properties. In another of its method aspects, this invention is directed to a method for identifying multimeric ligand compounds possessing multibinding properties which method comprises: (a) identifying a library of ligands which bind to GABA receptors wherein each ligand contains at least one reactive functionality; (b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and (d) assaying the multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds possessing multibinding properties. The preparation of the multimeric ligand compound library is achieved by either the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b). Sequential addition is preferred when a mixture of different ligands is employed to ensure heterodimeric or multimeric compounds are prepared. Concurrent addition of the ligands occurs when at least a portion of the multimer compounds prepared are homomultimeric compounds. The assay protocols recited in (d) can be conducted on the multimeric ligand compound library produced in (c) above, or preferably, each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS). In one of its composition aspects, this invention is directed to a library of multimeric ligand compounds which may possess multivalent properties which library is prepared by the method comprising: (a) identifying a ligand or a mixture of ligands which bind to GABA receptors wherein each ligand contains at least one reactive functionality; (b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands. In another of its composition aspects, this invention is directed to a library of multimeric ligand compounds which bind to GABA receptors which may possess multivalent properties which library is prepared by the method comprising: (a) identifying a library of ligands which bind to GABA receptors wherein each ligand contains at least one reactive functionality; (b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands. In a preferred embodiment, the library of linkers employed in either the methods or the library aspects of this invention is selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization, and/or polarability and amphiphilic linkers. For example, in one embodiment, each of the linkers in the linker library may comprise linkers of different chain length and/or having different complementary reactive groups. Such linker lengths can preferably range from about 2 to 100A. In another preferred embodiment, the ligand or mixture of ligands is selected to have reactive functionality at different sites on the ligands in order to provide for a range of orientations of said ligand on said multimeric ligand compounds. Such reactive functionality includes, by way of example, carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides,pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, boronates, anhydrides, and precursors thereof. It is understood, of course, that the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand. In other embodiments, the multimeric ligand compound is homomeric (i.e., each of the ligands is the same, although it may be attached at different points) or heterodimeric (i.e., at least one of the ligands is different from the other ligands). In addition to the combinatorial methods described herein, this invention provides for an iterative process for rationally evaluating what molecular constraints impart multibinding properties to a class of multimeric compounds or ligands targeting the GABA receptors. Specifically, this method aspect is directed to a method for identifying multimeric ligand compounds possessing multibinding properties with respect to the GABA receptors which method comprises: (a) preparing a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which target the GABA receptors with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; (b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multibinding properties; (c) repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties; (d) evaluating what molecular constraints imparted multibinding properties to the multimeric compound or compounds found in the first iteration recited in (a)- (c) above; (e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibinding properties to the multimeric compound or compounds found in said first iteration; (f) evaluating what molecular constraints imparted enhanced multibinding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above; (g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints. Preferably, steps (e) and (f) are repeated at least two times, more preferably at from 2-50 times, even more preferably from 3 to 50 times, and still more preferably at least 5-50 times. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates examples of multibinding compounds comprising 2 ligands attached in different forms to a linker. Figure 2 illustrates examples of multibinding compounds comprising 3 ligands attached in different forms to a linker. Figure 3 illustrates examples of multibinding compounds comprising 4 ligands attached in different forms to a linker. Figure 4 illustrates examples of multibinding compounds comprising 5-10 ligands attached in different forms to a linker. DETAILED DESCRIPTION OF THE INVENTION This invention is directed to multibinding compounds which are agonists, partial agonists, inverse agonists or antagonists of the GABA receptors, pharmaceutical compositions containing such compounds and methods for treating or preventing various disorders, including anxiety, depression, panic disorders, sleep and seizure disorders, overdoses of benzodiazepine-type drugs, and emesis, producing sedation, hypnosis, retrograde amnesia and also for enhancing alertness and memory. When discussing such compounds, compositions or methods, the following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings. The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms ("lower alkyl"), and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, /.-propyl, /so-propyl, -butyl, tso-butyl, w-hexyl, rc-decyl, tetradecyl, and the like. The term "substituted alkyl" refers to an alkyl group as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl. The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH )CH 2 -) and the like. The term "substituted alkylene" refers to an alkylene group, as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy. aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, - SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused groups contain from 1 to 3 fused ring structures. The term "alkaryl" refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like. The term "alkoxy" refers to the groups alkyl-O-, alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferred alkoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, π-propoxy, zsopropoxy, »-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, /2-hexoxy, 1,2-dimethylbutoxy, and the like. The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein. The term "alkylalkoxy" refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way of example, methylenemethoxy (-CH 2 OCH 3 ), ethylenemethoxy (-CH 2 CH 2 OCH 3 ), /z-propylene-.so-propoxy (-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene-t-butoxy (-CH 2 -O-C(CH 3 ) 3 ) and the like. The term "alkylthioalkoxy" refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene- S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylthioalkoxy groups are alkylene-S- alkyl and include, by way of example, methylenethiomethoxy (-CH 2 SCH 3 ), ethylenethiomethoxy (-CH 2 CH 2 SCH 3 ), tt-propylene-/so-thiopropoxy (-CH 2 CH 2 CH 2 SCH(CH 3 ) 2 ), methylene-t-thiobutoxy (-CH 2 SC(CH 3 ) 3 ) and the like. The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. Preferred alkenyl groups include ethenyl (-CH=CH 2 ), «-propenyl (-CH 2 CH=CH 2 ), tso-propenyl (-C(CH 3 )=CH 2 ), and the like. The term "substituted alkenyl" refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl. The term "alkenylene" refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., -CH 2 CH=CH- and -C(CH 3 )=CH-) and the like. The term "substituted alkenylene" refers to an alkenylene group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, - SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl. Additionally, such substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group. The term "alkynyl" refers to a monoradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 20 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl (-C≡CH), propargyl (-CH 2 C≡CH) and the like. The term "substituted alkynyl" refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl. The term "alkynylene" refers to a diradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynylene groups include ethynylene (-C≡C-), propargylene (-CH 2 C≡C-) and the like. The term "substituted alkynylene" refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, - SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl and -SO -heteroaryl The term "acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl- C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic- C(O)- where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein. The term "acylamino" or "aminocarbonyl" refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein. The term "aminoacyl" refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein. The term "aminoacyloxy" or "alkoxycarbonylamino" refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl. aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein. The term "acyloxy" refers to the groups alkyl-C(O)0-, substituted alkyl- C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)0-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein. The term "aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, - SO 2 -aryl, -SO 2 -heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above. The term "arylene" refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1 ,2-phenylene, 1,3- phenylene, 1 ,4-phenylene, 1 ,2-naphthylene and the like. The term "amino" refers to the group -NH 2 . The term "substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that both R's are not hydrogen. The term "carboxyalkyl" or "alkoxycarbonyl" refers to the groups "-C(O)O-alkyl", "-C(O)O-substituted alkyl", "-C(O)O-cycloalkyl", "-C(O)O- substituted cycloalkyl", "-C(O)O-alkenyl", "-C(O)O-substituted alkenyl", "-C(O)O-alkynyl" and "-C(O)O-substituted alkynyl" where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl alkynyl are as defined herein. The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like. The term "substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -S0 2 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl. The term "cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like. The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl and -SO 2 -heteroaryl. The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo. The term "heteroaryl" refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring). Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, - SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, -SO 2 -heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl. The term "heteroaryloxy" refers to the group heteroaryl-O-. The term "heteroarylene" refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridiylene, 1,2-quinolinylene, 1,8- quinolinylene, 1 ,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl and the like. The term "heterocycle" or "heterocyclic" refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substιtuted alkyl, - SO 2 -aryl and -SO 2 -heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, and the like. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles. The term "heterocyclooxy" refers to the group heterocyclic-O-. The term "thioheterocyclooxy" refers to the group heterocyclic-S- The term "heterocyclene" refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-morpholino, 2, 5 -morpholino and the like. The term "oxyacylamino" or "aminocarbonyloxy" refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein. The term "spiro-attached cycloalkyl group" refers to a cycloalkyl group attached to another ring via one carbon atom common to both rings. The term "thiol" refers to the group -SH. The term "thioalkoxy" refers to the group -S-alkyl. The term "substituted thioalkoxy" refers to the group -S-substituted alkyl. The term "thioaryloxy" refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above. The term "thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above. As to any of the above groups which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non- feasible. In addition, the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds, whether the isomers are those arising in the ligands, the linkers, or the multivalent constructs including the ligands and linkers. The term "pharmaceutically-acceptable salt" refers to salts which retain the biological effectiveness and properties of the multibinding compounds of this invention and which are not biologically or otherwise undesirable. In many cases, the multibinding compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(^o-propyl) amine, tri(n- propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, /?-toluene-sulfonic acid, salicylic acid, and the like. The term "pharmaceutically-acceptable cation" refers to the cation of a pharmaceutically-acceptable salt. The term "protecting group" or "blocking group" refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl- diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzyl groups, and the like. Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxycarbonyl (FMOC), allyloxycarbonyl (ALOC), and the like which can be removed by conventional conditions compatible with the nature of the product. Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild conditions compatible with the nature of the product. The term "optional" or "optionally" means that the subsequently described event, circumstance or substituent may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. The term "ligand" as used herein denotes a compound that is an agonist, partial agonist, inverse agonist, inverse partial agonist, or antagonist of the GABA receptors. The specific region or regions of the ligand that is (are) recognized by the receptor is designated as the "ligand domain". A ligand may be either capable of binding to a receptor by itself, or may require the presence of one or more non- ligand components for binding (e.g., Ca "2 , Mg "2 or a water molecule is required for the binding of a ligand to various ligand binding sites). Examples of ligands useful in this invention are described herein. Those skilled in the art will appreciate that portions of the ligand structure that are not essential for specific molecular recognition and binding activity may be varied substantially, replaced or substituted with unrelated structures (for example, with ancillary groups as defined below) and, in some cases, omitted entirely without affecting the binding interaction. The primary requirement for a ligand is that it has a ligand domain as defined above. It is understood that the term ligand is not intended to be limited to compounds known to be useful in binding to GABA receptors (e.g., known drugs). Those skilled in the art will understand that the term ligand can equally apply to a molecule that is not normally associated with receptor binding properties. In addition, it should be noted that ligands that exhibit marginal activity or lack useful activity as monomers can be highly active as multivalent compounds because of the benefits conferred by multivalency. The term "multibinding compound or agent" refers to a compound that is capable of multivalency, as defined below, and which has 2-10 ligands covalently bound to one or more linkers which may be the same or different. Multibinding compounds provide a biological and/or therapeutic effect greater than the aggregate of unlinked ligands equivalent thereto which are made available for binding. That is to say that the biological and/or therapeutic effect of the ligands attached to the multibinding compound is greater than that achieved by the same amount of unlinked ligands made available for binding to the ligand binding sites (receptors). The phrase "increased biological or therapeutic effect" includes, for example: increased affinity, increased selectivity for target, increased specificity for target, increased potency, increased efficacy, decreased toxicity, improved duration of activity or action, decreased side effects, increased therapeutic index, improved bioavailability, improved pharmacokinetics, improved activity spectrum, and the like. The multibinding compounds of this invention will exhibit at least one and preferably more than one of the above-mentioned effects. The term "potency" refers to the minimum concentration at which a ligand is able to achieve a desirable biological or therapeutic effect. The potency of a ligand is typically proportional to its affinity for its ligand binding site. In some cases, the potency may be non-linearly correlated with its affinity. In comparing the potency of two drugs, e.g., a multibinding agent and the aggregate of its unlinked ligand, the dose-response curve of each is determined under identical test conditions (e.g., in an in vitro or in vivo assay, in an appropriate animal model). The finding that the multibinding agent produces an equivalent biological or therapeutic effect at a lower concentration than the aggregate unlinked ligand is indicative of enhanced potency. The term "univalency" as used herein refers to a single binding interaction between one ligand as defined herein with one ligand binding site as defined herein. It should be noted that a compound having multiple copies of a ligand (or ligands) exhibits univalency when only one ligand is interacting with a ligand binding site. Examples of univalent interactions are depicted below. The term "multivalency" as used herein refers to the concurrent binding of from 2 to 10 linked ligands (which may be the same or different) and two or more corresponding receptors (ligand binding sites) on one or more receptors which may be the same or different. For example, two ligands connected through a linker that bind concurrently to two ligand binding sites would be considered as bivalency; three ligands thus connected would be an example of trivalency. An example of trivalent binding, illustrating a multibinding compound bearing three ligands versus a monovalent binding interaction, is shown below: Univalent Interaction Trivalent Interaction It should be understood that all compounds that contain multiple copies of a ligand attached to a linker or to linkers do not necessarily exhibit the phenomena of multivalency, i.e., that the biological and/or therapeutic effect of the multibinding agent is greater than the sum of the aggregate of unlinked ligands made available for binding to the ligand binding site (receptor). For multivalency to occur, the ligands that are connected by a linker or linkers have to be presented to their ligand binding sites by the linker(s) in a specific manner in order to bring about the desired ligand-orienting result, and thus produce a multibinding event. The term "selectivity" or "specificity" is a measure of the binding preferences of a ligand for different ligand binding sites (receptors). The selectivity of a ligand with respect to its target ligand binding site relative to another ligand binding site is given by the ratio of the respective values of K d (i.e., the dissociation constants for each ligand-receptor complex) or, in cases where a biological effect is observed below the K d , the ratio of the respective EC^ 0 's (i.e., the concentrations that produce 50% of the maximum response for the ligand interacting with the two distinct ligand binding sites (receptors)). The term "ligand binding site" denotes the site on the GABA receptors that recognizes a ligand domain and provides a binding partner for the ligand. The ligand binding site may be defined by monomeric or multimeric structures. This interaction may be capable of producing a unique biological effect, for example, agonism, antagonism, modulatory effects, may maintain an ongoing biological event, and the like. The terms "agonism" and "antagonism" are well known in the art. Ligands which are full agonists are ligands which when bound trigger the maximum activity seen by the natural ligands. Ligands which are partial agonists are ligands which when bound trigger sub-maximum activity. Ligands which are antagonists are ligands that when bound, inhibit or prevent the activity arising from a natural ligand binding to the receptor. Antagonists may be of the surmountable class (results in the parallel displacement of the dose-response curve of the agonist to the right in a dose dependent fashion without reducing the maximal response for the agonist) or insurmountable class (results in depression of the maximal response for a given agonist with or without the parallel shift). Ligands which are inverse agonists are ligands that, when bound, decrease the basal activity of the unbound receptor or which provide an activity opposive of the natural agonist. Ligands have measurable properties that relate to the interaction of the ligand and the receptor. These include the affinity of the ligand for the receptor, which relates to the energetics of the binding, the efficacy of the ligand for the receptor, which relates to the functional downstream activity of the ligand, the kinetics of the ligand for the receptor, which defines the onset of action and the duration of action, and the desensitization of the receptor for the ligand. Selectivity defines the ratio of the affinity and/or efficacy of a ligand across two receptors. The term "modulatory effect" refers to the ability of the ligand to change the activity of an agonist or antagonist through binding to a ligand binding site. It is a combination of these properties which provides the foundation for defining the nature of the functional response. It should be recognized that the ligand binding sites of the receptor that participate in biological multivalent binding interactions are constrained to varying degrees by their intra- and inter-molecular associations (e.g., such macromolecular structures may be covalently joined to a single structure, noncovalently associated in a multimeric structure, embedded in a membrane or polymeric matrix, and so on) and therefore have less translational and rotational freedom than if the same structures were present as monomers in solution. The term "inert organic solvent" means a solvent which is inert under the conditions of the reaction being described in conjunction therewith including, by way of example only, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, t-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert solvents. The term "treatment" refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes: (i) preventing the pathologic condition from occurring in a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the disease condition; (ii) inhibiting the pathologic condition, i.e., arresting its development; (iii) relieving the pathologic condition, i.e., causing regression of the pathologic condition; or (iv) relieving the conditions mediated by the pathologic condition. The term "pathologic condition which is modulated by treatment with a ligand" covers all disease states (i.e., pathologic conditions) which are generally acknowledged in the art to be usefully treated with a ligand for the GABA receptors in general, and those disease states which have been found to be usefully treated by a specific multibinding compound of our invention. Such disease states include, by way of example only, the prevention or treatment of anxiety, depression, sleep and seizure disorders, emesis, and overdoses of benzodiazepine-type drugs, and enhancing alertness and the like. "Emesis"is the act or instance of vomiting. An "emetic agent" is an agent that induces vomiting. Emesis also includes nausea. In this invention, emetic agents include compounds used in chemotherapy and radiation therapy. "Chemotherapy induced emesis" refers to emetic episodes which are induced by exposure to chemotherapy and/or anti-cancer treatments such as treatment with, for example, cisplatin, adriamycin, apomorphine, cyclohexamide, cyclophosphamide, copper sulphate, ipecacuanha, mustine and radiation, among others. Chemotherapy induced emetic episodes may be acute or may be delayed up to several days. There are generally three types of chemotherapy-induced emesis: acute, delayed and anticipatory (conditioned). Acute chemotherapy induced nausea and vomiting generally is considered to be that which occurs within the first 24 hours following drug administration. Delayed emesis is generally defined as emetic episodes starting about 24 hours or more following the last treatment. Conditioned or anticipatory emesis results from poor control of acute or delayed emesis. It is typically associated with anxiety prior to the next dose of chemotherapy, followed by nausea or vomiting before, during or possibly after the administration of chemotherapy. The term "therapeutically effective amount" refers to that amount of multibinding compound which is sufficient to effect treatment, as defined above, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term "linker", identified where appropriate by the symbol X, X' or X", refers to a group or groups that covalently links from 2 to 10 ligands (as identified above) in a manner that provides for a compound capable of multivalency. Among other features, the linker is a ligand-orienting entity that permits attachment of multiple copies of a ligand (which may be the same or different) thereto. In some cases, the linker may itself be biologically active. The term "linker" does not, however, extend to cover solid inert supports such as beads, glass particles, fibers, and the like. But it is understood that the multibinding compounds of this invention can be attached to a solid support if desired. For example, such attachment to solid supports can be made for use in separation and purification processes and similar applications. The term "library" refers to at least 3, preferably from 10 2 to 10 9 and more preferably from 10 2 to 10 " * multimeric compounds. Preferably, these compounds are prepared as a multiplicity of compounds in a single solution or reaction mixture which permits facile synthesis thereof. In one embodiment, the library of multimeric compounds can be directly assayed for multibinding properties. In another embodiment, each member of the library of multimeric compounds is first isolated and, optionally, characterized. This member is then assayed for multibinding properties. The term "collection" refers to a set of multimeric compounds which are prepared either sequentially or concurrently (e.g., combinatorially). The collection comprises at least 2 members; preferably from 2 to 10 9 members and still more preferably from 10 to 10 4 members. The term "multimeric compound" refers to compounds comprising from 2 to 10 ligands covalently connected through at least one linker which compounds may or may not possess multibinding properties (as defined herein). The term "pseudohalide" refers to functional groups which react in displacement reactions in a manner similar to a halogen. Such functional groups include, by way of example, mesyl, tosyl, azido and cyano groups. Lirikers The extent to which multivalent binding is realized depends upon the efficiency with which the linker or linkers that joins the ligands presents these ligands to the array of available ligand binding sites. Beyond presenting these ligands for multivalent interactions with ligand binding sites, the linker or linkers spatially constrains these interactions to occur within dimensions defined by the linker or linkers. Thus, the structural features of the linker (valency, geometry, orientation, size, flexibility, chemical composition, etc.) are features of multibinding agents that play an important role in determining their activities. The linkers used in this invention are selected to allow multivalent binding of ligands to the ligand binding sites of GABA receptors, wherever such sites are located on the receptor structure. The ligands are covalently attached to the linker or linkers using conventional chemical techniques providing for covalent linkage of the ligand to the linker or linkers. Reaction chemistries resulting in such linkages are well known in the art and involve the use of complementary functional groups on the linker and ligand. Preferably, the complementary functional groups on the linker are selected relative to the functional groups available on the ligand for bonding or which can be introduced onto the ligand for bonding. Again, such complementary functional groups are well known in the art. For example, reaction between a carboxylic acid of either the linker or the ligand and a primary or secondary amine of the ligand or the linker in the presence of suitable, well-known activating agents results in formation of an amide bond covalently linking the ligand to the linker; reaction between an amine group of either the linker or the ligand and a sulfonyl halide of the ligand or the linker results in formation of a sulfonamide bond covalently linking the ligand to the linker; and reaction between an alcohol or phenol group of either the linker or the ligand and an alkyl or aryl halide of the ligand or the linker results in formation of an ether bond covalently linking the ligand to the linker. Table I below illustrates numerous complementary reactive groups and the resulting bonds formed by reaction there between. Table I Representative Complementary Binding Chemistries First Reactive Group Second Reactive Group Linkage hydroxyl isocyanate urethane amine epoxide β-hydroxyamine sulfonyl halide amine sulfonamide carboxyl amine amide hydroxyl alkyl/aryl halide ether aldehyde amine/NaCNBH 4 amine ketone amine/NaCNBH 4 amine amine isocyanate carbamate The linker is attached to the ligand at a position that retains ligand domain- ligand binding site interaction and specifically which permits the ligand domain of the ligand to orient itself to bind to the ligand binding site. Such positions and synthetic protocols for linkage are well known in the art. The term linker embraces everything that is not considered to be part of the ligand. The relative orientation in which the ligand domains are displayed derives from the particular point or points of attachment of the ligands to the linker, and on the framework geometry. The determination of where acceptable substitutions can be made on a ligand is typically based on prior knowledge of structure-activity relationships (SAR) of the ligand and/or congeners and/or structural information about ligand-receptor complexes (e.g., X-ray crystallography, NMR, and the like). Such positions and the synthetic methods for covalent attachment are well known in the art. Following attachment to the selected linker (or attachment to a significant portion of the linker, for example 2-10 atoms of the linker), the univalent linker-ligand conjugate may be tested for retention of activity in the relevant assay. At present, it is preferred that the multibinding agent is a bivalent compound, e.g., two ligands which are covalently linked to linker X. Methodology The linker, when covalently attached to multiple copies of the ligands, provides a biocompatible, substantially non-immunogenic multibinding compound. The biological activity of the multibinding compound is highly sensitive to the valency, geometry, composition, size, flexibility or rigidity, etc. of the linker and, in turn, on the overall structure of the multibinding compound, as well as the presence or absence of anionic or cationic charge, the relative hydrophobicity/hydrophilicity of the linker, and the like on the linker. Accordingly, the linker is preferably chosen to maximize the biological activity of the multibinding compound. The linker may be chosen to enhance the biological activity of the molecule. In general, the linker may be chosen from any organic molecule construct that orients two or more ligands to their ligand binding sites to permit multivalency. In this regard, the linker can be considered as a "framework" on which the ligands are arranged in order to bring about the desired ligand- orienting result, and thus produce a multibinding compound. For example, different orientations can be achieved by including in the framework groups containing mono- or polycyclic groups, including aryl and/or heteroaryl groups, or structures incorporating one or more carbon-carbon multiple bonds (alkenyl, alkenylene, alkynyl or alkynylene groups). Other groups can also include oligomers and polymers which are branched- or straight-chain species. In preferred embodiments, rigidity is imparted by the presence of cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, heterocyclic, etc.). In other preferred embodiments, the ring is a six or ten member ring. In still further preferred embodiments, the ring is an aromatic ring such as, for example, phenyl or naphthyl. Different hydrophobic/hydrophilic characteristics of the linker as well as the presence or absence of charged moieties can readily be controlled by the skilled artisan. For example, the hydrophobic nature of a linker derived from hexamethylene diamine (H 2 N(CH 2 ) 6 NH 2 ) or related polyamines can be modified to be substantially more hydrophilic by replacing the alkylene group with a poly(oxyalkylene) group such as found in the commercially available "Jeffamines". Examples of molecular structures in which the above bonding patterns could be employed as components of the linker are shown below. The identification of an appropriate framework geometry and size for ligand domain presentation are important steps in the construction of a multibinding compound with enhanced activity. Systematic spatial searching strategies can be used to aid in the identification of preferred frameworks through an iterative process. Core structures other than those shown here can be used for determining the optimal framework display orientation of the ligands. The process may require the use of multiple copies of the same central core structure or combinations of different types of display cores. The above-described process can be extended to trimers and compounds of higher valency. Assays of each of the individual compounds of a collection generated as described above will lead to a subset of compounds with the desired enhanced activities (e.g., potency, selectivity, etc.). The analysis of this subset using a technique such as Ensemble Molecular Dynamics will provide a framework orientation that favors the properties desired. A wide diversity of linkers is commercially available (see, e.g., Available Chemical Directory (ACD)). Many of the linkers that are suitable for use in this invention fall into this category. Other can be readily synthesized by methods well known in the art and/or are described below. Having selected a preferred framework geometry, the physical properties of the linker can be optimized by varying the chemical composition thereof. The composition of the linker can be varied in numerous ways to achieve the desired physical properties for the multibinding compound. For example, by adjusting the hydrophobicity or hydrophilicity of the linker, the ability of the compounds to cross the blood-brain barrier can be modified. It can therefore be seen that there is a plethora of possibilities for the composition of a linker. Examples of linkers include aliphatic moieties, aromatic moieties, steroidal moieties, peptides, and the like. Specific examples are peptides or polyamides, hydrocarbons, aromatic groups, ethers, lipids, cationic or anionic groups, or a combination thereof. Examples are given below, but it should be understood that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. For example, properties of the linker can be modified by the addition or insertion of ancillary groups into or onto the linker, for example, to change the solubility of the multibinding compound (in water, fats, lipids, biological fluids, etc.), hydrophobicity, hydrophilicity, linker flexibility, antigenicity, stability, and the like. For example, the introduction of one or more poly(ethylene glycol) (PEG) groups onto or into the linker enhances the hydrophilicity and water solubility of the multibinding compound, increases both molecular weight and molecular size and, depending on the nature of the unPEGylated linker, may increase the in vivo retention time. Further PEG may decrease antigenicity and potentially enhances the overall rigidity of the linker. Ancillary groups which enhance the water solubility/hydrophilicity of the linker and, accordingly, the resulting multibinding compounds are useful in practicing this invention. Thus, it is within the scope of the present invention to use ancillary groups such as, for example, small repeating units of ethylene glycols, alcohols, polyols (e.g., glycerin, glycerol propoxylate, saccharides, including mono-, oligosaccharides, etc.), carboxylates (e.g., small repeating units of glutamic acid, acrylic acid, etc.), amines (e.g., tetraethylenepentamine), and the like) to enhance the water solubility and/or hydrophilicity of the multibinding compounds of this invention. In preferred embodiments, the ancillary group used to improve water solubility/hydrophilicity will be a polyether . The incorporation of lipophilic ancillary groups within the structure of the linker to enhance the lipophilicity and/or hydrophobicity of the multibinding compounds described herein is also within the scope of this invention. Lipophilic groups useful with the linkers of this invention include, by way of example only, aryl and heteroaryl groups which, as above, may be either unsubstituted or substituted with other groups, but are at least substituted with a group which allows their covalent attachment to the linker. Other lipophilic groups useful with the linkers of this invention include fatty acid derivatives which do not form bilayers in aqueous medium until higher concentrations are reached. Also within the scope of this invention is the use of ancillary groups which result in the multibinding compound being incoφorated or anchored into a vesicle or other membranous structure such as a liposome or a micelle. The term "lipid" refers to any fatty acid derivative that is capable of forming a bilayer or a micelle such that a hydrophobic portion of the lipid material orients toward the bilayer while a hydrophilic portion orients toward the aqueous phase. Hydrophilic characteristics derive from the presence of phosphato, carboxylic, sulfato, amino, sulfhydryl, nitro and other like groups well known in the art. Hydrophobicity could be conferred by the inclusion of groups that include, but are not limited to, long chain saturated and unsaturated aliphatic hydrocarbon groups of up to 20 carbon atoms and such groups substituted by one or more aryl, heteroaryl, cycloalkyl, and or heterocyclic group(s). Preferred lipids are phosphglycerides and sphingolipids, representative examples of which include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidyl-ethanolamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoyl-phosphatidylcholine or dilinoleoylphosphatidylcholine could be used. Other compounds lacking phosphorus, such as sphingolipid and glycosphingolipid families are also within the group designated as lipid. Additionally, the amphipathic lipids described above may be mixed with other lipids including triglycerides and sterols. The flexibility of the linker can be manipulated by the inclusion of ancillary groups which are bulky and/or rigid. The presence of bulky or rigid groups can hinder free rotation about bonds in the linker or bonds between the linker and the ancillary group(s) or bonds between the linker and the functional groups. Rigid groups can include, for example, those groups whose conformational lability is restrained by the presence of rings and/or multiple bonds within the group, for example, aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocyclic groups. Other groups which can impart rigidity include polypeptide groups such as oligo- or polyproline chains. Rigidity may also be imparted by internal hydrogen bonding or by hydrophobic collapse. Bulky groups can include, for example, large atoms, ions (e.g., iodine, sulfur, metal ions, etc.) or groups containing large atoms, polycyclic groups, including aromatic groups, non-aromatic groups and structures incoφorating one or more carbon-carbon multiple bonds (i.e., alkenes and alkynes). Bulky groups can also include oligomers and polymers which are branched- or straight-chain species. Species that are branched are expected to increase the rigidity of the structure more per unit molecular weight gain than are straight-chain species. In preferred embodiments, rigidity is imparted by the presence of cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, heterocyclic, etc.). In other preferred embodiments, the linker comprises one or more six-membered rings. In still further preferred embodiments, the ring is an aryl group such as, for example, phenyl or naphthyl. Rigidity can also be imparted electrostatically. Thus, if the ancillary groups are either positively or negatively charged, the similarly charged ancillary groups will force the presenter linker into a configuration affording the maximum distance between each of the like charges. The energetic cost of bringing the like-charged groups closer to each other will tend to hold the linker in a configuration that maintains the separation between the like-charged ancillary groups. Further ancillary groups bearing opposite charges will tend to be attracted to their oppositely charged counteφarts and potentially may enter into both inter- and intramolecular ionic bonds. This non-covalent mechanism will tend to hold the linker into a conformation which allows bonding between the oppositely charged groups. The addition of ancillary groups which are charged, or alternatively, bear a latent charge when deprotected, following addition to the linker, including deprotection of a carboxyl, hydroxyl, thiol or amino group by a change in pH, oxidation, reduction or other mechanisms known to those skilled in the art which result in removal of the protecting group, is within the scope of this invention. In view of the above, it is apparent that the appropriate selection of a linker group providing suitable orientation, restricted/unrestricted rotation, the desired degree of hydrophobicity/hydrophilicity, etc. is well within the skill of the art. Eliminating or reducing antigenicity of the multibinding compounds described herein is also within the scope of this invention. In certain cases, the antigenicity of a multibinding compound may be eliminated or reduced by use of groups such as, for example, poly(ethylene glycol). As explained above, the multibinding compounds described herein comprise 2-10 ligands attached to a linker that links the ligands in such a manner that they are presented to the receptor for multivalent interactions with ligand binding sites thereon therein. The linker spatially constrains these interactions to occur within dimensions defined by the linker. This and other factors increases the biological activity of the multibinding compound as compared to the same number of ligands made available in monobinding form. The compounds of this invention are preferably represented by the empirical formula (L) p (X) q where L, X, p and q are as defined above. This is intended to include the several ways in which the ligands can be linked together in order to achieve the objective of multivalency, and a more detailed explanation is described below. As noted previously, the linker may be considered as a framework to which ligands are attached. Thus, it should be recognized that the ligands can be attached at any suitable position on this framework, for example, at the termini of a linear chain or at any intermediate position. The simplest and most preferred multibinding compound is a bivalent compound which can be represented as L-X-L, where each L is independently a ligand which may be the same or different and each X is independently the linker. Examples of such bivalent compounds are provided in Figure 1 where each shaded circle represents a ligand. A trivalent compound could also be represented in a linear fashion, i.e., as a sequence of repeated units L-X-L-X-L, in which L is a ligand and is the same or different at each occurrence, as can X. However, a trimer can also be a radial multibinding compound comprising three ligands attached to a central core, and thus represented as (L) 3 X, where the linker X could include, for example, an aryl or cycloalkyl group. Illustrations of trivalent and tetravalent compounds of this invention are found in Figures 2 and 3 respectively where, again, the shaded circles represent ligands. Tetravalent compounds can be represented in a linear array, e.g., L-X-L-X-L-X-L in a branched array, e.g., L-X-L-X-L L (a branched construct analogous to the isomers of butane - /.-butyl, / ' so-butyl, sec- butyl, and t-butyl) or in a tetrahedral array, e.g., where X and L are as defined herein. Alternatively, it could be represented as an alkyl, aryl or cycloalkyl derivative as above with four (4) ligands attached to the core linker. The same considerations apply to higher multibinding compounds of this invention containing 5-10 ligands, as illustrated in Figure 4. However, for multibinding agents attached to a central linker such as aryl or cycloalkyl, there is a self-evident constraint that there must be sufficient attachment sites on the linker to accommodate the number of ligands present; for example, a benzene ring could not directly accommodate more than 6 ligands, whereas a multi-ring linker (e.g.. biphenyl) could accommodate a larger number of ligands. Certain of the above described compounds may alternatively be represented as cyclic chains of the form: X X and variants thereof. All of the above variations are intended to be within the scope of the invention defined by the formula (L) (X) . With the foregoing in mind, a preferred linker may be represented by the following formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - in which: m is an integer of from 0 to 20; X at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(S), -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of: -S-S- or a covalent bond; in which: n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. Additionally, the linker moiety can be optionally substituted at any atom therein by one or more alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic group. In one embodiment of this invention, the linker (i.e., X, X' or X") is selected from those shown in Table II: Table II Representative Linkers Linker -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 )-C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 2 -C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 3 -C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 4 -C(0)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 5 -C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 6 -C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) -C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 8 -C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 9 -C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 10 -C(O)-NH-(CH 2 ) 2 -NH- -H -(CH 2 ) 2 -NH-C(O)-(CH 2 ) u -C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 12 -C(O)-NH-(CH 2 ) 2 -NH- Linker -HN-(CH 2 ) 2 -NH-C(O)-Z-C(O)-NH-(CH 2 ) 2 -NH- where Z is 1,2-phenyl -HN-(CH 2 ) 2 -NH-C(O)-Z-C(O)-NH-(CH 2 ) 2 -NH- where Z is 1,3-phenyl -HN-(CH 2 ) 2 -NH-C(O)-Z-C(O)-NH-(CH 2 ) 2 -NH- where Z is 1,4-phenyl -HN-(CH 2 ) 2 -NH-C(O)-Z-O-Z-C(O)-NH-(CH 2 ) 2 -NH- where Z is 1,4-phenyl -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 2 -CH(NH-C(O)-(CH 2 ) 8 -CH 3 )-C(O)-NH-(CH 2 ),- NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 )-O-(CH 2 )-C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-Z-C(O)-NH-(CH 2 ) 2 -NH- where Z is 5-( /-octadecyloxy)- 1,3-phenyl -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 2 -CH(NH-C(O)-Z)-C(O)-NH-(CH 2 ) ,-NH- where Z is 4-biphenyl -HN-(CH 2 ) 2 -NH-C(O)-Z-C(O)-NH-(CH 2 ) 2 -NH- where Z is 5-(n-butyloxy)- 1,3-phenyl -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 8 -tra/.s-(CH=CH)-C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) ,-NH-C(O)-(CH 2 ) 2 -CH(NH-C(O)-(CH 2 ) p -CH 3 )-C(O)-NH-(CH 2 ),- NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 2 -CH(NH-C(O)-Z)-C(O)-NH-(CH 2 ) 2 -NH- where Z is 4-(n-octyl)-phenyl -HN-(CH 2 )-Z-O-(CH 2 ) 6 -O-Z-(CH 2 )-NH- where Z is 1,4-phenyl -HN-(CH 2 ),-NH-C(O)-(CH 2 ) 2 -NH-C(O)-(CH 7 ) 3 -C(O)-NH-(CH 7 ) 2 -C(O)-NH- (CH 2 ) 2 -NH- HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 2 -CH(NH-C(O)-Ph)-C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) ,-NH-C(O)-(CH 2 )-N+((CH,) 9 -CH 3 )(CH 2 -C(O)-NH-(CH 2 ) 2 -NH 2 )- (CH 2 )-C(O)-NH-(CH 2 ) 2 -NH- -H -(CH 2 ) 2 -NH-C(O)-(CH 2 )-N((CH 2 ) 9 -CH 3 )-(CH 2 )-C(0)-NH-(CH 2 ) 2 -NH- -HN-(CH,) ,-NH-C(O)-(CH 7 ) ,-NH-C(O)-(CH,) 2 -NH-C(O)-(CH,) 3 -C(O)-NH- (CH 2 ) 2 -C(O)-NH-(CH 2 ) 2 -C(θ " )-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-Z-C(O)-NH-(CH 2 ) 2 -NH- where Z is 5 -hydroxy- 1,3 -phenyl In another embodiment of this invention, the linker (i.e., X, X' or X") has the formula: wherein each R a is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene and arylene; each R b is independently selected from the group consisting of hydrogen, alkyl and substituted alkyl; and n ' is an integer ranging from 1 to about 20. In view of the above description of the linker, it is understood that the term "linker" when used in combination with the term "multibinding compound" includes both a covalently contiguous single linker (e.g., L-X-L) and multiple covalently non-contiguous linkers (L-X-L-X-L) within the multibinding compound. Ligands Any compound which is an agonist, partial agonist, inverse agonist, partial inverse agonist or antagonist of the GABA receptors and which can be covalently linked to a linker as described herein can be used as a ligand in this invention. As discussed in further detail below, numerous such receptor agonists, partial agonists, inverse agonists, partial inverse agonists, and antagonists are known in the art and any of these known compounds or derivatives thereof may be employed as ligands in this invention. GΔBA A GABA A receptors are generally ligand-gated chloride ion channels. These are heteropentameric complexes with subunits held together non-covalently, and arranged pseudosymmetrically around a central core. A high level of structural diversity exists because of the presence in each receptor of at least three different subunits, each derived from one of five structurally distinct and genetically different families, (6), β (3), γ(3), δ (1) and e (1) genes. GABA affinity and efficacy (multiple levels of chloride ion conductance) is dependent on subunit composition. A high affinity GABA binding site is localized at the interface of the a and β subunits. The receptors include allosteric modulatory binding sites for benzodiazepines, barbiturates, neurosteroids and ethanol. The binding of a benzodiazepine agonist increases the channel opening frequency. Barbituates and neurosteroids increase the GABA A channel open time. Benzodiazepine-mediated amplification of GABA-gated current requires the presence of three different subunits. Subunits of class , isoform 6 contain the benzodiazepine recognition site. Subunits of class β, isoform 4 contain the GABA recognition site. Subunits of the class γ, isoform 3 are essential for full expression of benzodiazepine activity. Subunits of the class δ, isoform 1 are associated with high affinity for GABA A receptor agonists. When receptors include subunits of the class p, isoform 2, they are biculline-insensitive (GABAc) Examples of full agonists include diazepam, midazolam, chlordiazepoxide, triazolam, lorazepam, alprazolam, and are associated with anxiolytic activity, sedation, ataxia, tolerance, dependence and memory impairment. Examples of partial agonists include abecarnil (Schering, Sandoz) and other β-carboline deriviatives, bretazenil (Roche), clonazepam, FG8205 and other imidazobenzodiazepines, divaplon (RU32698) and other imidazo[l,2a]pyrimidines Gardner, Drug. Dev. Res., 12, 1-28 (1988)), alpidem and other imidazopyridines, pagoclone (Rhone-Poulenc) and imidazenil. They are generally known to possess anxiolytic activity with considerably less side effects than the full agonists. Flumazenil is an example of an antagonist. FG7412 and RO 15-4513 are examples of partial inverse agonists, and RO19-4603, B-CCM and DMCM are examples of full inverse agonists. They are associated with anxiogenesis, confusion, agitation, aggression and memory enhancement. Some compounds are even subtype- selective, for example, the full agonist zolpidem (Synthelabo). The precise pharmacology observed for each compound is dependent on its degree of efficacy and its affinity at each GABA A receptor subtype. It has been postulated that there exists a physiological balance between engodenous agonists and inverse agonists. The balance can be disturbed by an increase in endogenous inverse agonism or a decrease in endogenous agonism, resulting in anxiety. Administration of agonists or partial agonists often restores the balance. GABAb GABAb receptors are G protein coupled 7TM receptors, and are negatively coupled to adenylate cyclase. Neuronal firing is inhibited via hypeφolarization (increased potassium ion conductance) or attenuation of neuro transmitter release (reduction in calcium ion influx). United States Patent No. 5,719,185 to Bountra, et al. discloses the use of GABA agonists having an agonist action at GABA B receptors in the treatment of emesis, for example, where the emesis is induced by cancer chemotherapeutic agents, radiation sickness, radiation therapy, poisons, toxins, pregnancy, vestibular disorders, post-operative sickness, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain, migraine, increased intercranial pressure, decreased intercranial pressure, or opioid analgesics. GABA B agonists are also known as being of use in the treatment of CNS disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome and as prokinetic and anti-tussive agents. Specific GABA agonists having an agonist action at GABA B receptors include 4-amino-3-(5-chloro-2-thienyl)butyric acid and those compounds generically and specifically disclosed in GB 1017439, e.g. baclofen, U.S. Pat. No. 4,656,298, e.g. 3-aminopropylphosphonous acid (3-aminopropylphosphinic acid), EP 0356128, i.e. 3-(aminopropyl)methyl phosphinic acid, and EP0463969, e.g. 3-(2-imidazolyl)-4-aminobutanoic acid which disclosures are incoφorated herein by reference. A particularly preferred compound for use in the present invention is baclofen. Baclofen, when used in the present invention, may be in the form of a mixture of isomers, for example a racemic mixture, or a separated isomer, i.e. the S(+) isomer or R(-) isomer. Preferably the R(-) isomer of baclofen is used. 2-OH saclofen and phaclofen are examples of selective antagonists. GABAc GABAc receptors are also ligand-gated chloride ion channels, more sensitive to GABA and less prone to desensitization, and with slower onset and offset times and longer duration of chloride channel open time compared with GABA A receptors. They are mainly expressed in the retina, cerebellum, hippocampus and cerebral cortex. They inhibit neuronal firing via hypeφolarization (chloride ion influx). They are bicuculline, phaclofen and benzodiazepine-insensitive. l,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid is an example of a selective antagonist. Typically, a compound selected for use as a ligand will have at least one functional group, such as an amino, hydroxyl, thiol or carboxyl group and the like, which allows the compound to be readily coupled to the linker. Compounds having such functionality are either known in the art or can be prepared by routine modification of known compounds using conventional reagents and procedures. The patents and publications set forth below provide numerous examples of suitably functionalized agonists, partial agonists, inverse agonists, partial inverse agonists and antagonists of the GABA receptors, and intermediates thereof, which may be used as ligands in this invention. A first group of preferred ligands for use in this invention are those ligands having formula A-F: Z.. J , R,_ 9 , R 8 ., R 2 . and R 2 » are as defined herein. Ligands of formula A-F (and the precursors thereof) are well-known in the art and can be readily prepared using art-recognized starting materials, reagents and reaction conditions. By way of illustration, the following patents and publications disclose compounds, intermediates and procedures useful in the preparation of ligands of formula A-F or related compounds suitable for use in this invention: U.S. Pat. Nos. 3,455,943; 4,312,870; 4,435,403; 4,596,808; 4,623,649; 4,713,383; 4,719,210; 4,999,353; 5,010,079; 5,1 16,841 ; 5,710,304; 5,719,185; 5,744,602; 5,744,603; 5,776,959; and 5,792,766; PCT publications WO 91/07407, WO 92/22552 and WO 9317025; EP 0 151 964, EP 0 181 282, EP 0 320 136, EP 0 344 943, EP 0 368 652, and German Patent No. DE 3,246,932. Costa, Neuropsychopharmacology. 4(4):225-235 (1991); Haefely et al., TIPS. 11 :452-456 (1990); Huang et al., ϊ. Med. Chem., 41(21):4130-4142 (1998); Jacobsen et al, J. Med. Chem, 42(7):1123-1 144 (1999); Knoflach et al, J. Pharmacol, and Exp. Therapeutics. 266(1):385-391 (1993); Liebigs Ann. Chem. 1986, 1749; Liu et al., J. Med. Chem.. 39(9):1928-1934 (1996); Massotti et al.. J. Pharmacol, and Exp. Therapeutics. 256(3): 1154-1 160 (1991); Mohler et al., Neurochemiπal Res.. 20(5):631-636 (1995); Nayeem et al., J. Neurochemistry. 62(2):815-818 (1994); Schoch et al., Biochem. Son Symp.. 59:121-134 (1993); Sieghart, TIPS. 13:446-450 (1992); Wafford et al., Am. Soc. Pharmacol, and Exp. Therapeutics. 43:240-244 (1992); Watjen et al., J. Med. Chem.. 32(10):2282-2291 (1989) Each of these patents and publications is incoφorated herein by reference in its entirety to the same extent as if each individual patent or publication was specifically and individually indicated to be incoφorated by reference in its entirety. Preparation of Multibinding Compounds The multibinding compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 , and references cited therein. The ligands can be covalently attached to the linker through any available position on the ligands, provided that when the ligands is attached to the linker (at least one of the linkers), the ligands retains its ability to bind to the GABA receptors, specifically at the benzadiazepine binding sites. The term linker refers to everything that is not considered to be part of the ligand. Covalent linkage with the linkers can contribute to reducing the dose of the ligand required to induce the desired therapeutic effect. This may result from, for example, increased ability for the GABA receptors, in affinity may be caused, for example, by changing the ligand efficacy of the GABA receptors (from a partial to a full agonist) and/or by altering the reversibility of binding. By altering the reversibility of binding, the multivalent compounds described herein may result in a longer duration of action. Certain sites of attachment of the linker to the ligand are preferred based on known structure-activity relationships (EP 0 573 982 Al by Walser et al., Gilman et al., J. Org. Chem., 58:3285-98 (1993); George et al., II Farmaco 46(Suppl l):277-288 (1991); Trapani et al., J. Med. Chem, 40:3109-3118 (1997); Hester and Von Voigtlander, J. Med. Chem, 22: 1390-98 (1979); Hester et al., J. Med. Chem.. 23:392-402 (1980); Hester et al, J. Med. Chem.. 23:873-77 (1980); and Hester et al, J. Med. Chem, 23:643-47 (1980), the contents of each of which are hereby incoφorated by reference. Preferably, the linker is attached to a site on the ligand where structure-activity studies show that a wide variety of substituents are tolerated without loss of receptor activity. For example, many known GABA receptor agonists, partial agonists, inverse agonists, partial inverse agonists and antagonists contain, among other structural features, a benzodiazepine group. Structure-activity studies show that only very minor modifications are tolerated on the benzodiazepine ring system, but that side chains can be present without adversely affecting the binding affinity for the GABA receptors. It will be understood by those skilled in the art that the following methods may be used to prepare other multibinding compounds of this invention. Ligand precursors, for example, ligands containing a leaving group or a nucleophilic group, can be covalently linked to a linker precursor containing a nucleophilic group or a leaving group, using conventional reagents and conditions. For example, two equivalents of ligand precursor with a halide, tosylate, or other leaving group, can be readily coupled to a linker precursor containing two nucleophilic groups, for example, amine groups, to form a dimer. The leaving group employed in this reaction may be any conventional leaving group including, by way of example, a halogen such as chloro, bromo or iodo, or a sulfonate group such as tosyl, mesyl and the like. When the nucleophilic group is a phenol, any base which effectively deprotonates the phenolic hydroxyl group may be used, including, by way of illustration, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, triethylamine, diisopropylethylamine and the like. Nucleophilic substitution reactions are typically conducted in an inert diluent, such as tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, 2- butanone, l-methyl-2-pyrrolidinone and the like. After the reaction is complete, the dimer is typically isolated using conventional procedures, such as extraction, filtration, chromatography and the like. By way of further illustration, dimers with a hydrophilic linker can be formed using a ligand precursor containing nucleophilic groups and a polyoxyethylene containing leaving groups, for example, poly(oxyethylene) dibromide (where the number of oxyethylene units is typically an integer from 1 to about 20). In this reaction, two molar equivalents of the ligand precursor are reacted with one molar equivalent of the poly(oxyethylene) dibromide in the presence of excess potassium carbonate to afford a dimer. This reaction is typically conducted in N,N-dimethylformamide at a temperature ranging from about 25 °C to about 100°C for about 6 to about 48 hours. Alternatively, the linker connecting the ligands may be prepared in several steps. Specifically, a ligand precursor can first be coupled to an "adapter", i.e., a bifunctional group having a leaving group at one end and another functional group at the other end which allows the adapter to be coupled to a intermediate linker group. In some cases, the functional group used to couple to the intermediate linker is temporarily masked with a protecting group ("PG"). Representative examples of adapters include, by way of illustration, tert-butyl bromoacetate, 1- Fmoc-2-bromoethylamine, l-trityl-2-bromoethanethiol, 4-iodobenzyl bromide, propargyl bromide and the like. After the ligand precursor is coupled to the adapter and the protecting group is removed from the adapter's functional group (if a protecting group is present) to form an intermediate, two molar equivalents of the intermediate are then coupled with an intermediate linker to form a dimer. Ligand precursors can be coupled with adapters which include both leaving groups and protecting groups to form protected intermediates. The leaving group employed in this reaction may be any conventional leaving group including, by way of example, a halogen such as chloro, bromo or iodo, or a sulfonate group such as tosyl, mesyl and the like. Similarly, any conventional protecting group may be employed including, by way of example, esters such as the methyl, tert- butyl, benzyl ("Bn") and 9-fluorenylmethyl ("Fm") esters. Protected intermediates can then be deprotected using conventional procedures and reagents to afford deprotected intermediates. For example, tert- butyl esters are readily hydrolyzed with 95% trifluoroacetic acid in dichloromethane; methyl esters can be hydrolyzed with lithium hydroxide in tetrahydrofuran water; benzyl esters can be removed by hydrogenolysis in the presence of a catalyst, such as palladium on carbon; and 9-fluorenylmethyl esters are readily cleaved using 20% piperidine in DMF. If desired, other well-known protecting groups and deprotecting procedures may be employed in these reactions to form deprotected intermediates. Similarly, ligand precursor having an adapter with an amine functional group can be prepared. Ligand precursors can be coupled with adapters which include leaving groups and protected amine groups to afford protected intermediates. The leaving group employed in this reaction may be any conventional leaving group. Similarly, any conventional amine protecting group may be employed including, by way of example, trityl, tert-butoxycarbonyl ("Boc"), benzyloxycarbonyl ("CBZ") and 9-fluorenylmethoxy-carbonyl ("Fmoc"). After coupling the adapter to the ligand precursor, the resulting protected intermediate is deprotected to afford a ligand precursor including an amine group using conventional procedures and reagents. For example, a trityl group is readily removed using hydrogen chloride in acetone; a Boc group is removed using 95% trifluoroacetic acid in dichloromethane; a CBZ group can be removed by hydrogenolysis in the presence of a catalyst, such as palladium on carbon; and a 9- fluorenylmethoxycarbonyl group is readily cleaved using 20% piperidine in DMF to afford the deblocked amine. Other well-known amine protecting groups and deprotecting procedures may be employed in these reactions to form amine- containing intermediates and related compounds. Ligand precursors having an adapter, for example, one including a free carboxylic acid group or a free amine group, can be readily coupled to intermediate linkers having complementary functional groups to form multibinding compounds as described herein. For example, when one component includes a carboxylic acid group, and the other includes an amine group, the coupling reaction typically employs a conventional peptide coupling reagent and is conducted under conventional coupling reaction conditions, typically in the presence of a trialkylamine, such as ethyldiisopropylamine. Suitable coupling reagents for use in this reaction include, by way of example, carbodiimides, such as ethyl-3-(3- dimethylamino)propylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and the like, and other well-known coupling reagents, such as N,N'-carbonyldiimidazole, 2-ethoxy-l-ethoxycarbonyl-l,2- dihydroquinoline (EEDQ), benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) and the like. Optionally, well- known coupling promoters, such N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBT), l-hydroxy-7-azabenzotriazole (HOAT), N,N-dimethylaminopyridine (DMAP) and the like, may be employed in this reaction. Typically, this coupling reaction is conducted at a temperature ranging from about 0°C to about 60 °C for about 1 to about 72 hours in an inert diluent, such as THF, to afford the dimer. The multibinding compounds described herein can also be prepared using a wide variety of other synthetic reactions and reagents. For example, ligand precursors having aryliodide, carboxylic acid, amine and boronic acid functional groups can be prepared. Hydroxymethyl pyrrole can be readily coupled under Mitsunobu reaction conditions to various phenols to provide, after deprotection, functionalized intermediates. The Mitsunobu reaction is typically conducted by reacting hydroxymethyl pyrrole and the appropriate phenol using diethyl azodicarboxylate (DEAD) and triphenylphosphine at ambient temperature for about 48 hours. Deprotection, if necessary, using conventional procedures and reagents then affords the functionalized intermediates. The functionalized intermediates can be employed in the synthesis of multibinding compounds. For example, aryliodide intermediates can be coupled with bis-boronic acid linkers to provide dimers. Typically, this reaction is conducted by contacting two molar equivalents of the aryliodide and one molar equivalent of the bis-boronic acid in the presence of tetrakis(triphenylphosphine)palladium(0), sodium carbonate and water in refluxing toluene. Aryliodide intermediates can also be coupled with acrylate intermediates or alkyne intermediate to afford dimers. These reactions are typically conducted by contacting two molar equivalents of aryliodide intermediates with one molar equivalent of either acrylates or alkynes in the presence of dichlorobis(triphenylphosphine)palladium (II), copper (I) iodide and diisopropylethylamine in N,N-dimethylformamide to afford the respective dimers. As will be readily apparent to those of ordinary skill in the art, the synthetic procedures described herein or those known in the art may be readily modified to afford a wide variety of compounds within the scope of this invention. Combinatorial Libraries The methods described herein lend themselves to combinatorial approaches for identifying multimeric compounds which possess multibinding properties. Specifically, factors such as the proper juxtaposition of the individual ligands of a multibinding compound with respect to the relevant array of binding sites on a target or targets is important in optimizing the interaction of the multibinding compound with its target(s) and to maximize the biological advantage through multivalency. One approach is to identify a library of candidate multibinding compounds with properties spanning the multibinding parameters that are relevant for a particular target. These parameters include: (1) the identity of ligand(s), (2) the orientation of ligands, (3) the valency of the construct, (4) linker length, (5) linker geometry, (6) linker physical properties, and (7) linker chemical functional groups. Libraries of multimeric compounds potentially possessing multibinding properties (i.e., candidate multibinding compounds) and comprising a multiplicity of such variables are prepared and these libraries are then evaluated via conventional assays corresponding to the ligand selected and the multibinding parameters desired. Considerations relevant to each of these variables are set forth below: Selection of Ligand(s) A single ligand or set of ligands is (are) selected for incoφoration into the libraries of candidate multibinding compounds which library is directed against a particular biological target or targets, i.e., binding to GABA receptors. The only requirement for the ligands chosen is that they are capable of interacting with the selected target(s). Thus, ligands may be known drugs, modified forms of known drugs, substructures of known drugs or substrates of modified forms of known drugs (which are competent to interact with the target), or other compounds. Ligands are preferably chosen based on known favorable properties that may be projected to be carried over to or amplified in multibinding forms. Favorable properties include demonstrated safety and efficacy in human patients, appropriate PK/ADME profiles, synthetic accessibility, and desirable physical properties such as solubility, logP, etc. However, it is crucial to note that ligands which display an unfavorable property from among the previous list may obtain a more favorable property through the process of multibinding compound formation; i.e., ligands should not necessarily be excluded on such a basis. For example, a ligand that is not sufficiently potent at a particular target so as to be efficacious in a human patient may become highly potent and efficacious when presented in multibinding form. A ligand that is potent and efficacious but not of utility because of a non- mechanism-related toxic side effect may have increased therapeutic index (increased potency relative to toxicity) as a multibinding compound. Compounds that exhibit short in vivo half-lives may have extended half-lives as multibinding compounds. Physical properties of ligands that limit their usefulness (e.g. poor bioavailability due to low solubility, hydrophobicity, hydrophilicity) may be rationally modulated in multibinding forms, providing compounds with physical properties consistent with the desired utility. Orientation: Selection of Ligand Attachment Points and Linking Chemistry Several points are chosen on each ligand at which to attach the ligand to the linker. The selected points on the ligand/linker for attachment are functionalized to contain complementary reactive functional groups. This permits probing the effects of presenting the ligands to their target binding site(s) in multiple relative orientations, an important multibinding design parameter. The only requirement for choosing attachment points is that attaching to at least one of these points does not abrogate activity of the ligand. Such points for attachment can be identified by structural information when available. For example, inspection of a co-crystal structure of a ligand bound to its target allows one to identify one or more sites where linker attachment will not preclude the ligand/target interaction. Alternatively, evaluation of ligand/target binding by nuclear magnetic resonance will permit the identification of sites non-essential for ligand/target binding. See, for example, Fesik, et al, U.S. Patent No. 5,891,643, the disclosure of which is incoφorated herein by reference in its entirety. When such structural information is not available, utilization of structure-activity relationships (SAR) for ligands will suggest positions where substantial structural variations are and are not allowed. In the absence of both structural and SAR information, a library is merely selected with multiple points of attachment to allow presentation of the ligand in multiple distinct orientations. Subsequent evaluation of this library will indicate what positions are suitable for attachment. It is important to emphasize that positions of attachment that do abrogate the activity of the monomeric ligand may also be advantageously included in candidate multibinding compounds in the library provided that such compounds bear at least one ligand attached in a manner which does not abrogate intrinsic activity. This selection derives from, for example, heterobivalent interactions within the context of a single target molecule. For example, consider a ligand bound to its target, and then consider modifying this ligand by attaching to it a second copy of the same ligand with a linker which allows the second ligand to interact with the same target at sites proximal to the first binding site, which include elements of the target that are not part of the formal ligand binding site and/or elements of the matrix surrounding the formal binding site, such as the membrane. Here, the most favorable orientation for interaction of the second ligand molecule may be achieved by attaching it to the linker at a position which abrogates activity of the ligand at the first binding site. Another way to consider this is that the SAR of individual ligands within the context of a multibinding structure is often different from the SAR of those same ligands in momomeric form. The foregoing discussion focused on bivalent interactions of dimeric compounds bearing two copies of the same ligand joined to a single linker through different attachment points, one of which may abrogate the binding/activity of the monomeric ligand. It should also be understood that bivalent advantage may also be attained with heterodimeric constructs bearing two different ligands that bind to common or different targets. Once the ligand attachment points have been chosen, one identifies the types of chemical linkages that are possible at those points. The most preferred types of chemical linkages are those that are compatible with the overall structure of the ligand (or protected forms of the ligand) readily and generally formed, stable and intrinsically innocuous under typical chemical and physiological conditions, and compatible with a large number of available linkers. Amide bonds, ethers, amines, carbamates, ureas, and sulfonamides are but a few examples of preferred linkages. Linker Selection In the library of linkers employed to generate the library of candidate multibinding compounds, the selection of linkers employed in this library of linkers takes into consideration the following factors: Valency: In most instances the library oflinkers is initiated with divalent linkers. The choice of ligands and proper juxtaposition of two ligands relative to their binding sites permits such molecules to exhibit target binding affinities and specificities more than sufficient to confer biological advantage. Furthermore, divalent linkers or constructs are also typically of modest size such that they retain the desirable biodistribution properties of small molecules. Linker Length: Linkers are chosen in a range of lengths to allow the spanning of a range of inter-ligand distances that encompaε the distance preferable for a given divalent interaction. In some instances the preferred distance can be estimated rather precisely from high-resolution structural information of targets. In other instances where high-resolution structural information is not available, one can make use of simple models to estimate the maximum distance between binding sites either on adjacent receptors or at different locations on the same receptor. In situations where two binding sites are present on the same target (or target subunit for multisubunit targets), preferred linker distances are 2-20 A, with more preferred linker distances of 3-12 A. In situations where two binding sites reside on separate target sites, preferred linker distances are 20-100 A, with more preferred distances of 30-70 A. Linker Geometry and Rigidity: The combination of ligand attachment site, linker length, linker geometry, and linker rigidity determine the possible ways in which the ligands of candidate multibinding compounds may be displayed in three dimensions and thereby presented to their binding sites. Linker geometry and rigidity are nominally determined by chemical composition and bonding pattern, which may be controlled and are systematically varied as another spanning function in a multibinding array. For example, linker geometry is varied by attaching two ligands to the ortho, meta, and para positions of a benzene ring, or in cis- or trα/.s-arrangements at the 1,1- vs. 1,2- vs. 1,3- vs. 1 ,4- positions around a cyclohexane core or in cis- or trα«5-arrangements at a point of ethylene unsaturation. Linker rigidity is varied by controlling the number and relative energies of different conformational states possible for the linker. For example, a divalent compound bearing two ligands joined by 1,8-octyl linker has many more degrees of freedom, and is therefore less rigid than a compound in which the two ligands are attached to the 4,4' positions of a biphenyl linker. Linker Physical Properties: The physical properties of linkers are nominally determined by the chemical constitution and bonding patterns of the linker, and linker physical properties impact the overall physical properties of the candidate multibinding compounds in which they are included. A range of linker compositions is typically selected to provide a range of physical properties (hydrophobicity, hydrophilicity, amphiphilicity, polarization, acidity, and basicity) in the candidate multibinding compounds. The particular choice of linker physical properties is made within the context of the physical properties of the ligands they join and preferably the goal is to generate molecules with favorable PK/ADME properties. For example, linkers can be selected to avoid those that are too hydrophilic or too hydrophobic to be readily absorbed and/or distributed in vivo. Linker Chemical Functional Groups: Linker chemical functional groups are selected to be compatible with the chemistry chosen to connect linkers to the ligands and to impart the range of physical properties sufficient to span initial examination of this parameter. Combinatorial Synthesis Having chosen a set of n ligands (n being determined by the sum of the number of different attachment points for each ligand chosen) and m linkers by the process outlined above, a library of (n\)m candidate divalent multibinding compounds is prepared which spans the relevant multibinding design parameters for a particular target. For example, an array generated from two ligands, one which has two attachment points (Al, A2) and one which has three attachment points (Bl, B2, B3) joined in all possible combinations provide for at least 15 possible combinations of multibinding compounds: Al-Al A1-A2 Al-Bl A1-B2 A1-B3 A2-A2 A2-B1 A2-B2 A2-B3 Bl-Bl B1-B2 B1-B3 B2-B2 B2-B3 B3-B3 When each of these combinations is joined by 10 different linkers, a library of 150 candidate multibinding compounds results. Given the combinatorial nature of the library, common chemistries are preferably used to join the reactive functionalies on the ligands with complementary reactive functionalities on the linkers. The library therefore lends itself to efficient parallel synthetic methods. The combinatorial library can employ solid phase chemistries well known in the art wherein the ligand and/or linker is attached to a solid support. Alternatively and preferably, the combinatorial libary is prepared in the solution phase. After synthesis, candidate multibinding compounds are optionally purified before assaying for activity by, for example, chromatographic methods (e.g., HPLC). Analysis of the Library Various methods are used to characterize the properties and activities of the candidate multibinding compounds in the library to determine which compounds possess multibinding properties. Physical constants such as solubility under various solvent conditions and logD/clogD values can be determined. A combination of NMR spectroscopy and computational methods is used to determine low-energy conformations of the candidate multibinding compounds in fluid media. The ability of the members of the library to bind to the desired target and other targets is determined by various standard methods, which include radioligand displacement assays for receptor and ion channel targets, and kinetic inhibition analysis for many enzyme targets. In vitro efficacy, such as for receptor agonists and antagonists, ion channel blockers, and antimicrobial activity, can also be determined. Pharmacological data, including oral absoφtion, everted gut penetration, other pharmacokinetic parameters and efficacy data can be determined in appropriate models. In this way, key structure-activity relationships are obtained for multibinding design parameters which are then used to direct future work. The members of the library which exhibit multibinding properties, as defined herein, can be readily determined by conventional methods. First those members which exhibit multibinding properties are identified by conventional methods as described above including conventional assays (both in vitro and in vivo). Second, ascertaining the structure of those compounds which exhibit multibinding properties can be accomplished via art recognized procedures. For example, each member of the library can be encrypted or tagged with appropriate information allowing determination of the structure of relevant members at a later time. See, for example, Dower, et al. International Patent Application Publication No. WO 93/06121 ; Brenner, et al, Proc. Natl. Acad. Sci, USA, 89:5181 (1992); Gallop, et al, U.S. Patent No. 5,846,839; each of which are incoφorated herein by reference in its entirety. Alternatively, the structure of relevant multivalent compounds can also be determined from soluble and untagged libaries of candidate multivalent compounds by methods known in the art such as those described by Hindsgaul, et al, Canadian Patent Application No. 2,240,325 which was published on July 11, 1998. Such methods couple frontal affinity chromatography with mass spectroscopy to determine both the structure and relative binding affinities of candidate multibinding compounds to receptors. The process set forth above for dimeric candidate multibinding compounds can, of course, be extended to trimeric candidate compounds and higher analogs thereof. Follow-up Synthesis and Analysis of Additional Libraries Based on the information obtained through analysis of the initial library, an optional component of the process is to ascertain one or more promising multibinding "lead" compounds as defined by particular relative ligand orientations, linker lengths, linker geometries, etc. Additional libraries can then be generated around these leads to provide for further information regarding structure to activity relationships. These arrays typically bear more focused variations in linker structure in an effort to further optimize target affinity and/or activity at the target (antagonism, partial agonism, etc.), and/or alter physical properties. By iterative redesign/analysis using the novel principles of multibinding design along with classical medicinal chemistry, biochemistry, and pharmacology approaches, one is able to prepare and identify optimal multibinding compounds that exhibit biological advantages towards their targets and as therapeutic agents. To further elaborate upon this procedure, suitable divalent linkers include, by way of example only, those derived from dicarboxylic acids, disulfonylhalides, dialdehydes, diketones, dihalides, diisocyanates, diamines, diols. mixtures of carboxylic acids, sulfonylhalides, aldehydes, ketones, halides, isocyanates, amines and diols. In each case, the carboxylic acid, sulfonylhalide, aldehyde, ketone, halide, isocyanate, amine and diol functional group is reacted with a complementary functionality on the ligand to form a covalent linkage. Such complementary functionality is well known in the art as illustrated in the following table: Representative Complementary Binding Chemistries First Reactive Group Second Reactive Group Linkage hydroxyl isocyanate urethane amine epoxide β-hydroxyamine sulfonyl halide amine sulfonamide carboxyl acid amine amide hydroxyl alkyl/aryl halide ether aldehyde amine(+ reducing agent) amine ketone amine(+ reducing agent) amine amine isocyanate carbamate Exemplary linkers include the following linkers identified as X-1 through 18 as set forth below: 11 lib X-50 X-61 X-62 77c lid lie 78 X-106 X-123 78b X-136 78c X-141 BUBSπTUTE SHEET (RULE 26) 78d X-178 X-179 X-180 79 79a SUBSTΓTUTE SHEET Diisocyanates SUBS TUTE SHEET (RULE 26) 80 SUBSTITUTE SUΠET (RULE 26) Diamines 80a X-285 H3C. "N- '/V « CH H 2 N, NH_ X-286 X-287 Afetf NH 2 X-298 X-299 80c X-306 X-312 X-314 80d X-323 X-324 X-325 81 X-333 X-335 X-336 X-337 X-344 81a OH HO HO ^ T T OH X-352 X-353 X-361 X-362 X-366 X-367 X-379 X-380 X-381 X-382 X-383 X-385 Dithiols X-386 X-387 X-388 SH X-390 81d δUBSTπum SHEET (RULE 26) Pharmaceutical Formulations When employed as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Preferred compounds are those which have receptor binding activity toward one or more GABA recertors at concentrations of less than 1 mM. This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh. 83 Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.001 to about 1 g, more usually about 1 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s). The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. 84 For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil. or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or 85 mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. The following formulation examples illustrate representative pharmaceutical compositions of the present invention. Formulation Example 1 Hard gelatin capsules containing the following ingredients are prepared: Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities. Formulation Example 2 A tablet formula is prepared using the ingredients below: Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 86 The components are blended and compressed to form tablets, each weighing 240 mg. Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components: Ingredient Weight % Active Ingredient 5 Lactose 95 The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in sterile water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 .0 mg Total 120 mg 87 The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50° to 60°C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Formulation Example 5 Capsules, each containing 40 mg of medicament are made as follows: Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. Formulation Example 6 Suppositories, each containing 25 mg of active ingredient are made as follows: Ingredient Amount Active Ingredient 25 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the 88 minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Formulation Example 7 Suspensions, each containing 50 mg of medicament per 5.0 mL dose are made as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (1 1%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water to 5.0 mL The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. Formulation Example 8 A formulation may be prepared as follows: Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425.0 mg quantities. 89 Formulation Example 9 A formulation may be prepared as follows: Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL Formulation Example 10 A topical formulation may be prepared as follows: Ingredient Quantity Active Ingredient 10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 e The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid. Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incoφorated by reference in its entirety. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Other suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985). 90 Utility The multibinding compounds of this invention are agonists, partial agonists, inverse agonists, partial inverse agonists or antagonists of the GABA receptors, which are known to mediate neurological disorders. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of various neurological disorders mediated by GABA receptors, such as anxiety, sleep and seizure disorders, and overdoses of benzodiazepine-type drugs, and enhancing alertness and the like. When used in treating or ameliorating such conditions, the compounds of this invention are typically delivered to a patient in need of such treatment by a pharmaceutical composition comprising a pharmaceutically acceptable diluent and an effective amount of at least one compound of this invention. The amount of compound administered to the patient will vary depending upon what compound and/or composition is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions are administered to a patient already suffering from, for example, anxiety, in an amount sufficient to at least partially reduce the symptoms. Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of the disorder in the patient, the age, weight and general condition of the patient, and the like. The pharmaceutical compositions of this invention may contain more than one compound of the present invention. As noted above, the compounds administered to a patient are in the form of pharmaceutical compositions described above which can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, etc. These compounds are effective as both injectable and oral deliverable pharmaceutical compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. The multibinding compounds of this invention can also be administered in the form of pro-drugs, i.e., as derivatives which are converted into a biologically active compound in vivo. Such pro-drugs will typically include compounds in which, for example, a carboxylic acid group, a hydroxyl group or a thiol group is converted to a biologically liable group, such as an ester, lactone or thioester group which will hydrolyze in vivo to reinstate the respective group. The compounds can be assayed to identify which of the multimeric ligand compounds possess multibinding properties. First, one identifies a ligand or mixture of ligands which each contain at least one reactive functionality and a library of linkers which each include at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand. Next, one prepares a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands with the library of linkers under conditions wherein the complementary functional groups react to form a covalent linkage between the linker and at least two of the ligands. The multimeric ligand compounds produced in the library can be assayed to identify multimeric ligand compounds which possess multibinding properties. The method can also be performed using a library of ligands and a linker or mixture of linkers. The preparation of the multimeric ligand compound library can be achieved by either the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands with the linkers. The multimeric ligand compounds can be dimeric, for example, homomeric or heteromeric. A heteromeric ligand compound library can be prepared by sequentially adding a first and second ligand. 92 Each member of the multimeric ligand compound library can be isolated from the library, for example, by preparative liquid chromatography mass spectrometry (LCMS). The linker or linkers can be flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and/or polarizability or amphiphilic linkers. The linkers can include linkers of different chain lengths and/or which have different complementary reactive groups. In one embodiment, the linkers are selected to have different linker lengths ranging from about 2 to 100A. The ligand or mixture of ligands can have reactive functionality at different sites on the ligands. The reactive functionality can be, for example, carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof, as long as the reactive functionality on the ligand is complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand. A library of multimeric ligand compounds can thus be formed which possesses multivalent properties. Multimeric ligand compounds possessing multibinding properties can be identified in an iterative method by preparing a first collection or iteration of multimeric compounds by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which target the GABA receptors with a linker or mixture of linkers, where the ligand or mixture of ligands includes at least one reactive functionality and the linker or mixture of linkers includes at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand. The ligand(s) and linker(s) are reacted under conditions which form a covalent linkage between the linker and at least two of the ligands. The first collection or iteration of multimeric compounds can be assayed to assess which if any of the compounds possess multibinding properties. The 93 process can be repeated until at least one multimeric compound is found to possess multibinding properties. By evaluating the particular molecular constraints which are imparted or are consistent with imparting multibinding properties to the multimeric compound or compounds in the first iteration, a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints can be assayed, and the steps optionally repeated to further elaborate upon said molecular constraints. For example, the steps can be repeated from between 2 and 50 times, more preferably, between 5 and 50 times. The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. Unless otherwise stated, all temperatures are in degrees Celsius. EXAMPLES In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. A = Angstroms cm = centimeter DCC = dicyclohexyl carbodiimide DMF = N, N-dimethy 1 form amide DMSO - dimethylsulfoxide EDTA = ethylenediaminetetraacetic acid g _ gram HPLC = high performance liquid chromatography MEM = minimal essential medium mg = milligram MIC - minimum inhibitory concentration min = minute mL = milliliter mm = millimeter mmol = millimol N = normal THF = tetrahydrofuran μL = microliters μm = microns 94 Example A: [ H]-flunitrazepam binding assay Experiments using H-diazepam or 3 H-flunitrazepam have demonstrated specific binding sites in CNS membrane preparations that satisfy the criteria for pharmacological receptors, e.g. saturability, reversibility, stereoselectivity and significant correlation with in vivo activities of the drugs in this class. Heterogeneity of benzodiazepine receptors has been reported (Klepner et al 1979, Supavilai and Karobath 1980, Hafely et al 1993, Davies et al 1994). Tissue preparation Male Wistar rats are decapitated and the brains rapidly removed. The cerebral cortices are removed, weighed and homogenized with a Potter-Elvejhem homogenizer in 20 volumes of ice-cold 0.32 M sucrose. This homogenate is centrifuged at 1000 g for 10 min. the pellet is discarded and the supernatant is centrifuged at 30,000 g for 20 min. The resulting membrane pellet is resuspended in 40 volumes of 0.05 M Tris buffer, pH 6.9. Assay 1 ml 0.05 Tris buffer, pH 6.9 560 ml H 2 O 70 ml 0.5 M Tris buffer, pH 6.9 50 ml 3 H-Flunitrazepam 20 ml vehicle (for total binding) or 0.1 mM Clonazepam (for non-specific binding) or appropriate drug concentrations. 300 ml tissue suspension. The tubes containing 3 H-flunitrazepam, buffer, drugs and H 2 O are incubated at 0-4°C in an ice bath. A 300 ml aliquot of the tissue suspension is added to the tubes at 10-second intervals. The timer is started with the addition of the mixture to the first tube. The tubes are then incubated at 0-4°C for 20 min and the 95 assay stopped by vacuum filtration through Whatman GF/B filters. This step is performed at 10-second intervals. Each filter is immediately rinsed with three 5 ml washes of ice-cold buffer, pH 6.9. The filters are counted in 10 ml of liquid scintillation counting cocktail. Evaluation Specific binding is defined as the difference between total binding and binding in the presence of clonazepam. Specific binding is approximately 97% of total ligand binding. The percent inhibition at each drug concentration is the mean of triplicate determinations. IC50 calculations are performed using log-probit analyses. References Chang RSL, Snyder SH (1978) Benzodiazepine receptors: labeling in intact animals with [ H]-flunitrazepam. Eur J Pharmacol 48:213-218 Damm HW, Miiller WE, Schlafer U, Wollert U (1978) [ 3 H]Flunitrazepam: its advantages as a ligand for the identification of benzodiazepine receptors in rat brain membranes. Res Commun Chem Pathol Pharmacol 22:597-600, Davies MF, Onaivi S, Chen SW, Maguire PA, Tsai NF, Loew GH (1994) Evidence for central benzodiazepine receptor heterogeneity from behavior tests. Pharmacol Biochem Behav 49:47-56 Hafely WE, Martin JR, Richard JG, Schoch P (1993) The multiplicity of actions of benzodiazepine receptor ligands. Can J Psychiatry 38. Suppl 4:S102-S108 Iversen LL (1983) Biochemical characterisation of benzodiazepine receptors. In: Trimble MR (ed.) Benzodiazepines Divided. John Wiley & Sons Ltd. pp 79- 85 Jacqmin P, Wibo M, Lesne M (1986) Classification of benzodiazepine receptor agonists, 96 inverse agonists and antagonists using bicuculline in an in vitro test. J Pharmacol (Paris) 17:139-145; Klepner CA, Lippa AS, Benson DI, Sano MC, Beer B (1979) Resolution in two biochemically and pharmacologically distinct benzodiazepine receptors. Pharmacol Biochem Behav. 11 :457-462 Mennini T, Garattini A (1982) Benzodiazepine receptors: Correlation with pharmacological responses in living animals. L_____L31 :2025-2035; Mδhler H, Okada T (1977) Benzodiazepine receptor: Demonstration in the central nervous system. Science 198:849- 851; Mόhler H, Okada T (1977) Properties of 3 H-diazepam binding to benzodiazepine receptors in rat cerebral cortex. Life Sci 20:2101-21 10; Mδhler H, Richards JG (1983) Benzodiazepine receptors in the central nervous system. In: Costa E (ed) The Benzodiazepines: From Molecular Biology to Clinical Practice. Raven Press, New York, pp. 93-116; Olsen RW (1981) GABA- benzodiazepine-barbiturate receptor interactions. J Neurochem 7:1-1 ; Schacht U, Baecker G (1982) Effects of clobazam in benzodiazepine- receptor binding assays Drug Dev. Res. Suppl. 1 , 83-93; Speth RC, Wastek GJ, Johnson PC, Yamamura HI (1978) Benzodiazepine binding in human brain: characterization using [ 3 H]flunitrazepam. Life Sci 22:859-866; Speth RC, Wastek GJ, Yamamura HI (1979) Benzodiazepine receptors: Temperature dependence of 3 H-diazepam binding. Ii_e___124:351-358; Squires RF, Braestrup C (1977) Benzodiazepine receptors in rat brain. NaJ_u_ 266:732-734; Supavilai P, Karobath M (1980) Heterogeneity of benzodiazepine receptors in rat cerebellum and hippocampus. Eur J Pharmacol 64:91-93; Sweetnam PM, Tallman JF (1985) Regional difference in brain benzodiazepine receptor carbohydrates. Mol Pharmacol 29: 299-306; Takeuchi T, Tanaka S, Rechnitz GA (1992) Biotinylated 1012— S conjugate as a probe ligand for benzodiazepine receptors: characterization of receptor binding sites and receptor assay for benzodiazepine drugs. Anal Biochem 203: 158-162;Tallman JF (1980) Interaction between GABA and benzodiazepines. Brain Res Bull 5:829-832 97 Example R: 6 CT flux Fresh cortical tissue is homogenized in 10 volumes of cold buffer A (mmol/1: NaCl 145, KC1 5, MgCl 2 4, KH 2 PO 4 1. Hepes 10, ATP 2, adjusted to pH 7.5 by 0.5M Tris-base) and centrifuged for 15mins at 770 g. The pellet is resuspended in buffer B (mmol/1: KC1 100, NaCl 45, the rest identical to buffer A) and again centrifuged for 15mins at 770 g. After another wash cycle in buffer A, the pellet is suspended to a protein concentration of 10.6mg/ml. Before measuring GABA- stimulated chloride flux, aliquots of the membrane suspension containing l .όmg of protein are preincubated with or without the benzodiazepine under investigation, dissolved in buffer A containing 0.2% BSA for lOmins at 30°C. A prewarmed GABA and radioactive chloride solution ( 36 G " ; New England Nuclear: 13.5mCi/g. lmCi/ml final concentration) is then added to a final volume of 400ml. The reaction mixture is vortexed briefly and incubated for 3s at 30°C. The flux is stopped by adding 4ml of cold buffer A containing lOOmM bicuculline and 0.01% BSA, immediately followed by filtration through Whatman GF/B filters presoaked in 0.1% polyethyleneimine. Tubes and filters are rinsed with 4ml of stop solution, and the filters are further washed with 10 portions of 1ml each. The radioactivity in the tissue retained on the filters is measured in a scintillation counter. Nonspecific flux in the absence of GABA is subtracted from each value to obtain the specific GABA-stimulated chloride flux. Further details of this procedure are described in Harris and Allan, Science, 228, 1108-11 10 (1985). Example C: Four plate test in mice The four plate test in mice has been described by Boissier et al (1968) as a method for the rapid screening of minor tranquilizers. Procedure The test box has the shape of a rectangle (25 x 18 x 16 cm). The floor is covered with 4 identical rectangular metal plates (8 >< 1 1 cm) separated from one another by a gap of 4 mm. The plates are connected to a source of continuous 98 current which applies to 2 adjacent plates a mild electrical shock of 0.35 Ma for 0.5 sec. This evokes a clear flight reaction of the animals. Adult male Swiss albino mice, weighing 17 to 23 g, are randomly divided into different groups. Thirty min before the test the animals are injected intraperitoneally with the test drug or the vehicle. At the beginning of the test, the mouse is gently dropped onto a plate and is allowed to explore the enclosure for 15 sec. After this, every time the animal crosses from one plate to another, the experimenter electrifies the whole floor for 0.5 sec, which evokes a clear flight-reaction of the mouse which often crosses 2 or 3 plates. If it continues running, no new shock is delivered during the following 3 min. Evaluation The number of times the apparatus is electrified is counted each minute for 10 min. The delivery of shocks decreases dramatically the motor activity. The number of shocks received during the first min is taken as parameter. This number is increased by minor tranquilizers, such as benzodiazepines, but not by neuroleptics and psychoanaleptics. Critical assessment of the method The test is of value to differentiate minor tranquilizers, such as benzodiazepine anxiolytics, from neuroleptics. References Aron et al., "Evaluation of a rapid technique for detecting minor tranquilizers," Neurophar acol., 10:459-469 (1971) Boissier et al., 'A new method for rapid screening of minor tranquilizers in mice." Eur. J. Pharmacol., 4:145-151 (1968) Lenegre et al., "Specificity of Piracetarrfs anti-amnesic activity in three models of amnesia in the mouse," Pharmacol Biochem Behav.. 29:625-629 (1988) 99 Simon, "Les Anxiolytiques. Possibilites d'etude chez 1'animal," Actualites pharmacol., 23:47-78 (1970) Stephens et al., "Abecarnil, a metabolically stable, anxioselective β-carboline acting at benzodiazepine receptors," J. Pharmacol. Exper. Ther. 253: 334-343 (1990) Example D: Eight-dark model In the light-dark model, exploration of mice or rats is inhibited by bright illumination, which is highly aversive for rodents (Crawley and Goodwin 1980). The animals are placed on the brightly lit side of a two compartment chamber, and the number of crossings between the light and dark sites are recorded. Anxiolytics produce a dose-dependent increase in crossings. Procedure One third of a cage (40 60 cm) is darkened with a cover and separated with a wall from the otherwise brightly illuminated area. A round hole (diameter 13 cm) allows the rat to pass from the illuminated to the darkened compartment. The cage is placed on an Animex ® -activity counter. The animals are treated orally with the test compound 30 min prior to the session. At the start of the test the rat is placed in the middle of the illuminated part of the cage. The number of crossings is registered during 10 min. Groups of 6-8 animals are used for each dose. Evaluation The average number of crossings in the treated groups are compared with the saline treated control. Critical assessment of the method It has been shown that a variety of anxiolytics, including diazepam, pentobarbital and meprobamate produce a dose-dependent increase in crossings, whereas non-anxiolytic agents do not have this facihtatory effect. Furthermore, the 100 relative potency of anxiolytics in increasing exploratory behavior in the two- compartment chamber agrees well with the potency found in clinical trials. References Barnes et al., "Profiles of R(+)/S(-)-Zacopride and anxiolytic agents in a mouse model," Eur. J. Pharmacol. 218:91-100 (1992) Barnes et al, "The effects of umespirone as a potential anxiolytic and antipsychotic agent," Pharmacol. Biochem. Behav., 40:89-96 (1991) Blumstein and Crawley, "Further characterisation of a simple, automated exploratory model for the anxiolytic effects of benzodiazepines," Pharmacol. Biochem. Behav., 18:37-40 (1983) Crawley, "Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines," Pharmacol. Biochem. Behav., 15:695-699 (1981) Crawley and Goodwin "Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines," Pharmacol. Biochem. Behav.. 13:167-170 (1980) Kauppila et al., "Effects of atipamezole, a novel a2 -adrenoreceptor antagonist, in open-field, plus-maze, two compartment exploratory, and forced swimming tests in rats," Eur. J. Pharmacol., 20 : 177- 182 ( 1991 ) Schipper et al., "Preclinical pharmacology of Flesinoxan: A potential anxiolytic and antidepressant drug," Human Psychopharmacol., 6:53-61 (1991) Treit, "Animal models for the study of anti-anxiety agents: A review," Neurosci. Biohehav. Reviews, 9:203-222 (1985) 101 Example E: Open field test Interruption of light beams as a measure of movements of rats or mice in a cage ("open field") has been used by many authors such as Dews (1953), Saelens et al. (1968) Nakatsu and Owen, (1980). Recently developed devices allow measurement of not only general motor activity but also locomotion, rearing and the speed of locomotion (Ericson et al 1991). Procedure The rats are observed in a square open field arena (68 68 x 45 cm) equipped with 2 rows of 8 photo cells, sensitive to infrared light, placed 40 and 125 mm above the floor, respectively. The photocells are spaced 90 mm apart and the last photocell in a row is spaced 25 mm from the wall. Measurements are made in the dark in a ventilated, sound-attenuating box. Interruptions of photocell beams can be collected by a microcomputer and the following variables can be evaluated: Motor activity: All interruptions of photo beams in the lower rows. Rearing: All interruption of the photo beams in the upper rows. Locomotion: Successive interruptions of photocells in the lower rows when the animal is moving in the same direction. Adult male Sprague-Dawley rats with a weight between 280 and 320 g are used. Drugs are injected subcutaneously 10 to 40 min. before test. The rats are observed for 15 min whereby counts per min. are averaged for 3 min intervals. References Barros et al., "Enhanced detection of hyperactivity after drug withdrawal with a simple modification of the open-field apparatus," J. Pharmacol. Meth. 26:269-275 (1991) Becker and Randall, "Effects of prenatal ethanol exposure in C57BL mice on locomotor activity and passive avoidance behavior," Psychopharmacol., 97:40-44 (1989) 102 Carlezon et al., "Reversal of both QNX-induced locomotion and habituation decrement is indicative of Ml agonist properties," Drug Dev. Res., 23:333-339 (1991) Choi et al., "Caffeine and theophylline analogues: correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors," Life Sci., 43:387-398 (1988) Crabbe et al., "Environmental variables differentially affect ethanol- stimulated activity in selectively bred mouse lines," Psychopharmacology 95:103-108 (1988) Crabbe et al., "Mice genetically selected for differences in open-field activity after ethanol," U 27:577-581 (1987) Crunelli and Bernasconi "A new device to measure different size movements: Studies on d-amphetamine-induced locomotion and stereotypy," J. Pharmacol. Meli 2:43-50 (1979) Dews, "The measurement of the influence of drugs on voluntary activity in mice," Br. J. Pharmacol., 8:46-48 (1953) Ericson et al., "Photocell measurements of rat motor activity" J. Pharmacol. Met , 25:111-122 (1991) Fontenay et al., "De trois tests de comportement du rat pour l'etude des medicaments psychotropes," J. Pharmacol., (Paris) 1 :243-254 (1970) Example F: Rotarod method The test is used to evaluate the activity of drugs interfering with motor coordination. In 1956, Dunham and Miya suggested that the skeletal muscle relaxation induced by a test compound could be evaluated by testing the ability of mice or rats to remain on a revolving rod. This forced motor activity has subsequently been used by many investigators. The dose which impairs the ability of 50%) of the mice to remain on the revolving rod is considered the endpoint. 103 Procedure The apparatus consists of a horizontal wooden rod or metal rod coated with rubber with 3 cm diameter attached to a motor with the speed adjusted to 2 rotations per minute. The rod is 75 cm in length and is divided into 6 sections by plastic discs, thereby allowing the simultaneous testing of 6 mice. The rod is in a height of about 50 cm above the table top in order to discourage the animals from jumping off the roller. Cages below the sections serve to restrict the movements of the animals when they fall from the roller. Male mice (CD-I Charles River strain) with an weight between 20 and 30 g undergo a pretest on the apparatus. Only those animals which have demonstrated their ability to remain on the revolving rod for at least 1 minute are used for the test. The test compounds are administered intraperitoneally or orally. Thirty minutes after intraperitoneal or 60 minutes after oral administration the mice are placed for 1 min on the rotating rod. The number of animals falling from the roller during this time is counted. Using different doses, ED 50 values can be calculated. More-over, testing at various time intervals, time- response curves can be obtained. Percent animals falling from the rotarod within the test period is calculated for every drug concentration tested. ED50 is defined as the dose of drug at which 50%) of the test animals fall from the rotarod. Critical assessment of the method Many central depressive drugs are active in this test. Benzodiazepines, such as diazepam and flurazepam, have ED 50 values below 1 mg/kg i.p. The activity of neuroleptics, such as chlorpromazine or haloperidol, is in the same range. In this way, the test does not really differentiate between anxiolytics and neuroleptics but can evaluate the muscle relaxant potency in a series of compounds such as the benzodiazepines. Moreover, the test has been used in toxicology for testing neurotoxicity. References Cartmell et al., "A revised rotarod procedure for measuring the effect of 104 antinociceptive drugs on motor function in the rat," J. Pharmacol. Meth. 26:149-159 (1991) Dunham and Miya "A note on a simple apparatus for detecting neurological deficit in rats and mice," J. Am. Pharmaceut. Assoc, 46:208-210 (1957) Novack and Zwolshen "Predictive value of muscle relaxant models in rats and cats," J. Pharmacol. Meth., 10: 175-183 (1983) Saeed and Wooles "Effect of chronically administered methylxanthines on ethanol-induced motor incoordination in mice," Life Sci., 39:1429-1437 (1986) Example G: Potentiation of hexobarbital sleeping time The test is used to elucidate CNS-active properties of drugs. Not only hypnotics, sedatives, and tranquilizers but also antidepressants at high doses are known to prolong hexobarbital induced sleep after a single dose of hexobarbital. The loss of righting reflex is measured as the criterion for the duration of hexobarbital-induced sleeping time. Mice are used in this test, since metabolic elimination of hexobarbital is rapid in this species. Procedure Groups of 10 male NMRI-mice with an average weight of 18-22 g are used. They are dosed orally, i.p. or s.c. with the test compound or the reference standard (e.g. 3 mg/kg diazepam p.o.) or the vehicle. Thirty min after i.p. or s.c. injection or 60 min after oral dosing, 60 mg/kg hexobarbital is injected intravenously. The animals are placed on their backs on a warmed (37°C pad and the duration of loss of the righting reflex (starting at the time of hexobarbital injection) is measured until they regain their righting reflexes. Injection of 60 mg/kg hexobarbital usually causes anesthesia for about 15 min. If there is any doubt as to the reappearance of the righting reflex, the subject is placed gently on its back again and, if it rights itself within one minute, this time is considered as the endpoint. ED^ is de-fined as the dose of drug leading to a 100%> prolongation in duration of anesthesia in 50% of the animals. 105 References Balazs and Grice, "The relationship between liver necrosis and pentobarbital sleeping time in rats," Toxicol. Appl. Pharmacol., 5:387-391 (1963) Harris and Uhle, "Enhancement of amphetamine stimulation and prolongation of barbiturate depression by a substituted pyrid[3,4-b] indole derivative," J Pharmacol. Exp. Ther. 132:251-257 (1961) Lim, "Animal techniques for evaluating hypnotics. In: Nodine JH Siegler PE (eds.) Animal and Clinical Pharmacologic Techniques in Drug Evaluation," Year Book Medical Publ., Inc., Chicago, pp 291-297 (1964) Mason, "Hypnotics and general anaesthetics. In: Laurence DR, Bacharach AL (eds) Evaluation of Drug Activities: Pharmacometrics. Academic Press, London and New York, pp 261-286 (1964) Example H: Withdrawal syndrome in dependent mice DBA 2J mice (12-20g) are treated orally twice daily with test compounds for 17 days. 5 hours after the last dose, the low efficacy benzodiazepine receptor inverse agonist, sarmazenil (Ro 15-3505), is injected into a tail vein of the conscious mice. Each mouse is then observed for 30mins for the appearance of tremor, wild running, clonic and/or tonic convulsions. Example T: Step-through This test uses normal behavior of mice and rats. These animals avoid bright light and prefer dim illumination. When placed into a brightly illuminated space connected to a dark enclosure, they rapidly enter the dark compartment and remain there. The standard technique was developed for mice by Jarvik and Kopp (1967) and modified for rats by King and Glasser (1970). It is widely used in testing the effects of memory active compounds (Fekete and de Wied. 1982, Hock and McGaugh, 1985, Hock et al 1989, Hock 1994). 106 Procedure Mice and rats of either sex are used. The test apparatus consists of a small chamber connected to a larger dark chamber via a guillotine door. The small chamber is illuminated with a 7 W/12 V bulb. The test animals are given an acquisition trial followed by a retention trial 24 h later. In the acquisition trial the animal is placed in the illuminated compartment at a maximal distance from the guillotine door, and the latency to enter the dark compartment is measured. Animals that do not step through the door within a cut-off time: 90 s (mice) or 180 sec (rats) are not used. Immediately after the animal enters the dark compartment, the door is shut automatically and an unavoidable footshock (Footshock: 1 mA; 1 sec - mice; 1.5 mA; 2 sec - rat) is delivered. The animal is then quickly removed (within 10 sec) from the apparatus and put back into its home cage. The test procedure is repeated with or without drug. The cut-off time on day 2 is 300 sec (mice) or 600 sec (rats), respectively. The time to step-through during the learning phase is measured and the time during the retention test is measured. In this test a prolongation of the step-through latencies is specific to the experimental situation. An increase of the step-through latency is defined as learning. References Banfi et al., "A screening method for substances potentially active on learning and memory," J. Pharmacol. Meth., 8:255-263 (1982) Fekete and deWied, "Potency and duration of action of the ACTH 4-9 analog (ORG 2766) as compared to ACTH 4-10 and [D-Phe 7 ]ACTH 4-10 on active and passive avoidance behavior of rats," Pharmacol. Biochem. Behav., 16:387-392 (1982) Fine et al, "Cholinergic ventral forebrain grafts into the neocortex improve passive avoidance memory in a rat model of Alzheimer disease,' Proc. Natl. Acad. Sci. USA, 82:5227-5230 (1985) 107 Fisher et al, "(±)-cis-2-Methyl-spiro( l,3-oxathiolane-5,3')quinuclidine, an Ml selective cholinergic agonist, attenuates cognitive dysfunctions in an animal model of Alzheimer's disease," J. Pharmacol. Exp. Ther., 257:392-403 (1991) Hock, "Involvement of nitric oxide formation in the action of losartan (DUP 753): effects in an inhibitory avoidance model," Behav. Brain. Res., 61 : 163-167 (1994) Hock et al., "Effects of the novel compound, Hoe 065, upon impaired learning and memory in rodents," Eur. J. Pharmacol., 171 :79-85 (1989) Hock and McGaugh, "Enhancing effects of Hoe 175 on memory in mice," Psychopharmacology, 86:1 14-1 17 (1985) Jarvik and Kopp, "An improved one-trial learning situation in mice," Psychol. Rep., 21 :221-224 (1967) King and Glasser, "Duration of electroconvulsive shock-induced retrograde amnesia in rats," Physiol. Behav., 5:335-339 (1970) Rush and Streit, "Memory modulation with peripherally acting cholinergic drugs," Psychopharmacology, 106: 375-382 (1992) Wan et al., "Changes in heart rate and body temperature during passive avoidance behavior in rats," Physiol. Behav.. 47:493-499 (1990) 108 PREPARATIVE EXAMPLES Example 1 : Preparation of 6-(2-bromophenyl)-8-fluoro-I-hydroxymethyl-4H- imidazo[l,5-a][l,4]benzodiazepine-3-carboxamide (3). Step 1. A mixture of 7-chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-l ,4- benzodiazepine-2-acetic acid, ethyl ester (Walser, A., et al, J. Heterocyclic Chem., 23, 1303-14 (1986); 4 mmols), Raney nickel (1.5 g), THF (40 mL), ethanol (4 mL, and 20%o ammonia (v/v) in methanol (0.4 L) is hydrogenated at atmospheric pressure until hydrogen consumption ceases. The catalyst is removed by filtration and the filtrate is concentrated. The residue is dissolved in methylene chloride (10 mL) and ethanol (10 mL) to which is added glycolaldehyde dimer (0.5 g). The solution is stirred for 120 minutes at which time activated Mn0 2 (1.5 g) is added and stirring is continued another hour. Solids are removed by filtration and the filtrate is concentrated to give crude product. The desired product is obtained in pure form after chromatography. Step 2. The product obtained from the preceding reaction is suspended in 6 N HCl (20 mL) and is heated on a steam bath until the reaction is complete as determined by TLC. The solution is evaporated under reduced pressure and the residue is digested in hot water (5 mL) containing sodium acetate (0.8 g), giving the crude product as a crystalline solid. Recrystallization from ethanol-water gives the pure carboxylic acid. 109 Step 3. A mixture of the carboxylic acid (3 mmols) from the preceding reaction with phosphorous pentachloride (4 mmols) in methylene chloride (75 mL) is stirred at room temperature for 3 hr. Ammonia gas is bubbled through the mixture until the mixture is basic. A concentrated aqueous ammonia solution (10 mL) is added and the mixture is stirred. The reaction is followed by TLC and when complete, the organic layer is separated, washed with water, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired product 3 is obtained after purification by HPLC. Example 2: Preparation of 8-chloro-l-methyI-4-hydroxymethyl-6-phenyl-4H- s-triazolo[4,3-a] [l,4]benzodiazepine (11). A solution of 8-chloro-l-methyl-6-phenyl-4H-s-triazolo[4,3- a][l,4]benzodiazepine-4-carboxylic acid, ethyl ester (Hester, Jr., J.B.; et al. J. Med Chem. 1980, 23, 643-7; 2 mmols) in THF (10 mL) is stirred with LiBH 4 (5 mmols) under an inert atmosphere at RT. The progress of the reaction is monitored by TLC and when the reaction is complete, water (1 mL) is added and the mixture stirred to destroy excess hydride reagent. Solvent is removed under reduced pressure and the residue is partitioned between water and CH 2 CU. The layers are separated and the aqueous layer is further extracted with CH 2 C1 2 . The combined organic extracts are dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired 8-chloro-l-methyl-4-hydroxymethyl-6-phenyl-4H-s- triazolo[4,3-a][l,4]benzodiazepine (11) is obtained by purification of the crude product with the use of HPLC. 110 Example 3: Preparation of a Formula I compound wherein p is 2, q is 1, and the ligand, L, is the benzodiazepine nucleus of imidazenil linked through the carboxamide group to the linker X. Formula I compound of type, A-Z-p P 2. E.P. 0 573 982 Al 111 A solution of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[l,5- a][l,4]benzodiazepine-3-carbonyl chloride (1, E.P. 0 573 982 Al; 2 mmols) in CH 2 C1 2 (5 mL) containing pyridine (0.5 mL) is stirred in an inert atmosphere. To this solution is added 1,6-diaminohexane (1 mmol) and stirring is continued. The progress of the reaction is monitored by TLC and when the reaction is complete, water and additional CH 2 C1 2 are added, the mixture is shaken, the layers are separated and the aqueous layer is further extracted with CH 2 C1 2 . The combined organic extracts are dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [2, wherein R = -(CH 2 ) 4 -; R, = H; R 8 = F; and R 2 , = Br] is obtained by purification of the crude product with the use of HPLC. Example 4: Preparation of a Formula I compound wherein p is 2, q is 1, and the ligand, L, is the benzodiazepine nucleus of imidazenil linked through a C-1 methylene group to the linker X. Formula I compound of type, B~ Z h — £__) — Z b ~B 1 12 Sodium hydride (2 mmols) is added to a solution of 6-(2-bromophenyl)-8- fluoro-hydroxymethyl-4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxamide (3, 2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 1, όdibromohexane (1 mmol) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 SO ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula 10 I compound [4, wherein R = -(CH 2 ) 4 -; RI = R2 - H; R 8 = F; and R2' = Br] is obtained by purification of the crude product with the use of HPLC. Example 5: Preparation of a Formula I compound wherein p is 2, q is 1, and the ligand, L, is the imidazopyridine nucleus of zolpidem linked through the 5 carboxamide group to the linker X. Formula I compound of type, C~ Z~ t M — Z~( A solution of 6-methyl-2-(4-methylphenyl)imidazo[ 1 ,2-a]pyridine-3-acetyl 30 chloride (5, Trapani, G.; et. al., J. Med. Chem. 1997, 40, 3109-18; 2 mmols) in 113 CH 2 C1 2 (5 mL) containing pyridine (0.5 mL) is stirred in an inert atmosphere. To this solution is added N,N-dimethyl-l,8-diaminooctane ( 1 mmol) and stirring is continued. The progress of the reaction is monitored by TLC and when the reaction is complete, water and additional CH,C1 2 are added, the mixture is shaken, the layers are separated and the aqueous layer is further extracted with CH 2 C1 2 . The combined organic extracts weredried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [6, wherein R = -(CH 2 ) 6 -; R 3 = R 5 = R 6 = CH 3 ] is obtained by purification of the crude product with the use of HPLC. 10 Example 6: Preparation of a Formula I compound wherein p is 2, q is 1, and the ligand, L, is the imidazopyridine nucleus of zolpidem linked through a C- 4' methylene group to the linker X. Formula I compound of type, D-Z^— y — Z d "D 15 Diethyl azodicarboxylate (2 mmol) is added dropwise via a syringe to a stirred solution of triphenylphosphine (2 mmol) in THF (5 mL) under an inert 30 atmosphere and at room temperature. To this is added a solution of N,N'-6- 114 trimethyl-2-(4-hydroxymethylphenyl)imidazo[ 1 ,2-a]pyridine-3-acetamide (7, Georges, P.; Allen, J. FR 25 81646 Al 8611 14; Chem. Abstr. 107, 5903 1; 2 mmol) and hvdroquinone (2 mmol) in THF (1 mL). The resulting solution is stirred at RT and the progress of the reaction is followed by TLC. After the reaction occurs, solvent is removed by evaporation under reduced pressure and the residue is purified by HPLC, giving the desired Formula I compound [8, wherein R = 1 ,4- C 6 H 4 -; R 3 = R 4 = R 6 = CH 3 ]- Example 7: Preparation of a Formula I compound wherein p is 2, q is 1, and the ligand, L, is the triazolobenzodiazepine nucleus of alprazolam linked through a C-1 methylene group to the linker X. A mixture of 8-chloro-l-chloromethyl-6-phenyl-4H-s-triazolo[4,3- a][1.4]benzodiazepine (9, Hester, Jr., J.B.; et al., J Med. Chem. 1980, 23, 392-402; 2 mmols), 1 ,4-diaminobutane (1 mmol), and KI (2 mmols) in THF (20 mL) is stirred under an inert atmosphere at RT. The progress of the reaction is monitored by TLC and when the reaction is complete, solvent is removed in vacuo. Water is 1 15 mixed with the residue and is extracted with CH 2 C1 2 . The organic extract is washed with half saturated brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [10, wherein R = -(CH 2 ) 2 -; R g - Cl; R 2 " = R, = H] is obtained by purification of the crude product with the use of HPLC. Example 8: Preparation of a Formula I compound wherein p is 2, q is 1, and the ligand, L, is the triazolobenzodiazepine nucleus of alprazolam linked through a C-4 methylene, group to the linker X. 11 Sodium hydride (2 mmols) is added to a solution of 8-chloro-l-methyl-4- hydroxymethyl-6-phenyl-4H-s-triazolo[4.3-a][l,4]benzodiazepine (11, 2 mmols) in dry DMF (1 mL) stirred under an inert atmosphere. To this is added a solution of 1 ,8-dibromooctane (1 mmol) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurred, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back- 1 16 washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [12, wherein R = -(CH 2 ) 6 -; R 8 ' = Cl; and R," = H] is obtained by purification of the crude product with the use of HPLC. Example 9: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L,, is the benzodiazepine nucleus of imidazenil linked through the carboxamide group to the linker X and the second ligand, L,, is the benzodiazepine nucleus of imidazenil linked through a C-1 methylene group. T 1 ^g. aq NaOH CB 1 + HNCH 2 — LRl— CH 2 OH *- 13 -*- TPP Step 1. A mixture of 6-(2-bromophenyl)-8-fluoro-4H-imιdazo[ l ,5-a][l ,4] benzodiazepine-3 -carbonyl chloride (1, E.P. 0 573 982 Al; 2 mmols), 3- aminopropan-1-ol (2 mmol) and ice with 50% aqueous NaOH is mixed vigorously and progress of the reaction is followed by TLC. When the reaction is complete, the mixture is extracted with diethyl ether. The combined ether extracts are washed 1 17 with water and with half-saturated brine, dried (Na j SO , filtered and concentrated under reduced pressure giving the crude product. The desired compound [13, wherein R = -CH 2 -; R, = H; R 8 = F; and R 2 , = Br] is obtained by purification of the crude product with the use of HPLC. Step 2. A solution, cooled to the temperature of an ice-water bath, containing compound 13 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5% NaHCO 3 , with water and with half-saturated brine. The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired compound (14, wherein R = -CH,-; R, = H; R 8 = F; and R 2 , = Br) is obtained by purification of the crude product by use of HPLC. Step 3. Sodium hydride (2 mmols) is added to a solution of 3 (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 14 (2 mmol) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts wereback-washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [15, wherein R = -CH 2 - ; R, = R 2 = H; R 8 = F; and R 2 ' = Br] is obtained by purification of the crude product with the use of HPLC. 118 Example 10: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the imidazopyridine nucleus of zolpidem linked through the carboxamide group to the linker X and a second ligand is the imidazopyridine nucleus linked through a C-4' methylene group. 17 Step 1. A mixture of 5 (2 mmols), N-methylethanolamine (2 mmol) and ice with 50%) aqueous NaOH is mixed vigorously and progress of the reaction is followed by TLC. When the reaction is complete, the mixture is extracted with diethyl ether. The combined ether extracts are washed with water and with half-saturated brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound (16, wherein R = single bond; R 3 = R 5 = R 6 = CH-,) is obtained by purification of the crude product with the use of HPLC. Step 2. A solution, cooled to the temperature of an ice-water bath, containing 1 19 compound 16 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5% NaHCO 3 , with water and with half-saturated brine. The organic layer is separated, dried (Na^O , filtered and concentrated under reduced pressure to give the crude product. The desired compound (17, wherein R = single bond; R 3 = R 5 = R 6 = CH 3 ) is obtained by purification of the crude product by use of HPLC. Step 3. Sodium hydride (2 mmols) is added to a solution of 7, (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 17 (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na^O , filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound (18, wherein R = single bond; R 3 = R 4 = R 5 = R 6 = CH 3 ) is obtained by purification of the crude product with the use of HPLC. Example 11: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the triazolobenzodiazepine nucleus of alprazolam linked through 120 a C-1 methylene group to the linker X and a second ligand, L 2 , is the triazolobenzodiazepine nucleus linked through a C-4 methylene group. Step 1. A mixture of 8-chloro-l-hydroxymethyl-6-phenyl-4H-s-triazolo[4,3-a] [l ,4]benzodiazepine (9, 2 mmols), N-methyl-6-amino-l -hexanol (2 mmols), and KI (2 mmols) in THF (20 mL) is stirred under an inert atmosphere at RT. The progress of the reaction is monitored by TLC and when the reaction is complete, solvent is removed in vacuo. Water is mixed with the residue and is extracted with CH 2 C1 2 . The organic extract is washed with half saturated brine, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [19, wherem R = -(CH,) 4 -; R g ' = Cl; R 2 " = R 9 = H] is obtained by purification of the crude product with the use of HPLC. Step 2. A solution, cooled to the temperature of an ice-water bath, containing 121 compound 19 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5%o NaHCO 3 , with water and with half-saturated brine. The organic layer is separated, dried (Na 2 SO ), filtered and concentrated under reduced pressure to give the crude product. The desired compound [20, wherein wherein R - -(CH 2 ) 4 -; R s - Cl; R 2 " = R 9 = H] is obtained by purification of the crude product by use of HPLC. Step 3. Sodium hydride (2 mmols) is added to a solution of 1 1, (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 20 (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts wereback-washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [21 , wherein R = - (CH 2 ) 4 -; R 8 ' = Cl; R 2 " = R, = H] is obtained by purification of the crude product with the use of HPLC. 122 Example 12: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the benzodiazepine nucleus of imidazenil linked through the carboxamide group to the linker X and a second ligand, L 2 , is the imidazopyridine nucleus of zolpidem linked through the carboxamide group. " 3 aq NaOH N 2 H 4 - H 2 0 HNCH : 2 — -CH o 2 NPhtal — *~ 22 »- EtOH A solution of 6-methyl-2-(4-methylphenyl)imidazo[l ,2-]pyridine-3-acetyl chloride (5, 2 mmols) in CH 2 C1 2 (5 mL) containing pyridine (0.5 mL) is stirred in an inert atmosphere. To this solution is added N-methyl-N'-phthalimidoyl-l ,3- diaminopropane (2 mmols) and stirring is continued. The progress of the reaction is monitored by TLC and when the reaction is complete, water and additional CH,C1 2 are added, the mixture is shaken, the layers are separated and the aqueous layer is further extracted with CH 2 C1 2 . The combined organic extracts are dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound [22, wherein R (CH 2 )-; R 3 = R 5 = R b = CH 3 ] is obtained by purification of the crude product with the use of HPLC. 123 Step 2. A mixture of 22 (2 mmols) and hydrazine hydrate (4 mmols) in absolute ethanol is warmed to 75 °C and stirred under an inert atmosphere. The progress of the reaction is monitored by TLC and when the reaction is complete, the mixture is cooled in an ice bath and the solids collected by filtration. The solids are washed with ethanol and CH 2 C1 2 . The combined filtrates are mixed with cold half- saturated brine and extracted with CH 2 C1 2 . The combined organic layers washed with water, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound [23, wherein R = -(CH 2 )-; R, = R 5 = R 6 = CH 3 ] is obtained by purification of the crude product with the use of HPLC. Step 3. A solution of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[l ,5- a][l,4]benzodiazepine-3-carbonyl chloride (1 , 2 mmols) in CH,C1 2 (5 mL) containing pyridine (0.5 mL) is stirred in an inert atmosphere. To this solution is added a solution of 23 (2 mmols) in CH 2 C1 2 (5 mL) and stirring is continued. The progress of the reaction is monitored by TLC and when the reaction is complete, water and additional CH 2 C1 2 are added, the mixture is shaken, the layers are separated and the aqueous layer is further extracted with CH 2 C1 2 . The combined organic extracts are dried (Na^SO , filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [23, wherein R = -(CH 2 )-; R 3 = R 5 = R 6 = CH 3 ; R s = F; and R 2 , = Br] is obtained by purification of the crude product with the use of HPLC. 124 Example 13: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the benzodiazepine nucleus of imidazenil linked through the carboxamide group to the linker X and a second ligand, L,, is the imidazopyridine nucleus of zolpidem linked through a C-4' methylene group. R ι +_ aα NaOH CBr, + HNCH 2 — ^-CH 2 OH 25 TPP Step 1. A mixture of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[l,5- a][l,4]benzodiazepine-3 -carbonyl chloride (1, 2 mmols), 6-amino-l-hexanol (2 mmols) and ice with 50% aqueous NaOH is mixed vigorously and progress of the reaction is followed by TLC. When the reaction is complete, the mixture is extracted with diethyl ether. The combined ether extracts are w ashed with w ater and with half-saturated brine, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound [25, wherein R -(CH 2 ) 4 -; R, = H; R 8 = F; and R 2 . = Br] is obtained by purification of the crude product with the use of HPLC. 125 Step 2. A solution, cooled to the temperature of an ice- water bath, containing compound 25 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5%> NaHCO 3 , with water and with half-saturated brine. The organic layer is separated, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired compound [26, wherein R = -(CH 2 ) 4 -; R, = H; R 8 = F; and R 2 ' = Br] is obtained by purification of the crude product by use of HPLC. Step 3. Sodium hydride (2 mmols) was added to a solution of 11 (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 26 (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [27, wherein R = - (CH 2 ) 4 -; R, = H; R 3 = R 4 = CH 3 ; R 8 = F; and R 2 ' = Br] is obtained by purification of the crude product with the use of HPLC. 126 Example 14: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the benzodiazepine nucleus of imidazenil linked through the carboxamide group to the linker X and a second ligand, L 2 , is the triazolobenzodiazepine nucleus of triazolam linked through a C-1 methylene group. 1 + H 2 NCH 2 -0-CH 2 NPhtal CHzC 28 ______ . Py EtOH Step 1. A solution of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[l,5-a][l,4] benzodiazepineaze-3-carbonyl chloride (1 , 2 mmols) and N-phthaloyl-2,2'- oxybis(ethylamine) (2 mmols) in CH 2 C1 2 (10 mL) and pyridine (0.5 mL) is stirred at RT and the progress of the reaction is followed by TLC. When the reaction is complete, water is added and the mixture is extracted with CH 2 C1 2 . The combined organic extracts are washed with water and with half-saturated brine, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound (28, wherein R = -CH,OCH 2 -; R, = H; R 8 = F; R 2 '= Br) is obtained by purification of the crude product with the use of HPLC. Step 2. 127 A mixture of 28 (2 mmols) and hydrazine hydrate (4 mmols) in absolute ethanol is warmed to 75 °C and stirred under an inert atmosphere. The progress of the reaction is monitored by TLC and when the reaction is complete, the mixture is cooled in an ice bath and the solids collected by filtration. The solids are washed with ethanol and CH 2 C1 2 . The combined filtrates are mixed with cold half- saturated brine and extracted with CH 2 C1 2 . The combined organic layers are washed with water, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound (29, wherein R = -CH 2 OCH 2 -; R, = H; R 8 = F; R 2 - Br) is obtained by purification of the crude product with the use of HPLC. Step 3. A mixture of 9 (2 mmols), 29 (2 mmols), and KI (2 mmols) in THF (20 mL) is stirrred under an inert atmosphere at RT. The progress of the reaction is monitored by TLC and when the reaction is complete, solvent is removed in vacuo. Water is mixed with the residue and is extracted with CH 2 C1 2 . The organic extract is washed with half saturated brine, dried (Na,S04), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound (30, wherein R = -CH 2 OCH 2 -; R, = H; R 8 = F; R 2 * = Br; R 8 ' = Cl; R," = H) is obtained by purification of the crude product with the use of HPLC. Example 15: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the benzodiazepine nucleus of imidazenil linked through the carboxamide group to the linker X and a second ligand, L : , is the 128 triazolobenzodiazepine nucleus of triazolam linked through a C-4 methylene group. 7' aq NaOH CBr Λ + HNCH 2 — CH 2 OH — »- 31 TPP Step 1. A mixture of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[l,5- a][l,4]benzodiazepine-3 -carbonyl chloride (1 , 2 mmols), 2-(2-aminoethoxy)ethanol (2 mmols) and ice with 50% aqueous NaOH is mixed vigorously and progress of the reaction is followed by TLC. When the reaction is complete, the mixture is extracted with diethyl ether. The combined ether extracts are washed with water and with half saturated brine, dried (Na^SO.,), filtered and concentrated under reduced pressure giving the crude product. The desired compound (31 , wherein R = -CH ; OCH,-; R, = H; R 8 = F; R 2 ' = Br) is obtained by purification of the crude product with the use of HPLC. Step 2. A solution, cooled to the temperature of an ice-water bath, containing 129 compound 31 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5% NaHCO 3 , with water and with half- saturated brine. The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired compound (32, wherein R = -CH 2 OCH 2 -; R, = H; R 8 = F; R 2 '= Br) is obtained by purification of the crude product by use of HPLC. Step 3. Sodium hydride (2 mmols) is added to a solution 11 (2 mmols) in dry DMF (3 mL) stirred under an inert atmosphere. To this is added a solution of 32 (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [33, wherein R = - CH 2 OCH 2 -; R, = H; R 8 = F; R 2 '= Br; R 8 , = Cl; R 2 " = H] is obtained by purification of the crude product with the use of HPLC. Example 16: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the benzodiazepine nucleus of imidazenil linked through a C-1 130 methylene group to the linker X and a second ligand, L 2 , is the imidazopyridine nucleus of zolpidem linked through the carboxamide group. R, CBr, + HNCH 2 -@-CH 2 OH ^^ 34 TPP Step 1. A mixture of 5 (2 mmols), N-methyl-6-aminohexanol (2 mmol) and ice with 50%) aqueous NaOH is mixed vigorously and progress of the reaction is followed by TLC. When the reaction is complete, the mixture is extracted with diethyl ether. The combined ether extracts are washed with water and with half-saturated brine, dried (Na 2 S04), filtered and concentrated under reduced pressure giving the crude product. The desired compound (34, wherein R = -(CH 2 ) 4 -; R 3 = R 5 = R 6 = CH,) is obtained by purification of the crude product with the use of HPLC. Step 2. A solution, cooled to the temperature of an ice-water bath, containing compound 34 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 m.L) is prepared and is stirred. The cooling bath is 131 removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5% NaHCO,, with water and with half-saturated brine. The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired compound (35, wherein R = -(CH 2 ) 4 -; R 3 = R 5 = R 6 = CH 3 ) is obtained by purification of the crude product by use of HPLC. Step 3. Sodium hydride (2 mmols) is added to a solution of 3 (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 35 (2 mmol) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL,) and the combined organic extracts are back- washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [36, wherein R = - (CH 2 ) 4 -; R, = R 2 = H; R 3 = R 5 = R 6 = CH 3 ; R 8 = F; and R 2 . = Br] is obtained by purification of the crude product with the use of HPLC. Example 17: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the imidazobenzodiazepine nucleus of imidazenil linked through 132 a C-1 methylene group to the linker X and a second ligand, L,, is the imidazopyridine nucleus of zolpidem linked through a C-4' methylene group. 3 + BrCH 2 -^-CH 2 OTMS - *. 37 U2-12. -. CB DMF H,0 TPP Sodium hydride (2 mmols) is added to a solution of 3 (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 6-bromo-l- hexanol-O-TMS (2 mmol) in dry DMF ( 1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 SO ), filtered and concentrated under reduced pressure giving the crude product. The desired compound (37, wherein R = - (CH 2 ) 4 -; R, = R 2 = H; R 8 = F; and R, - Br] is obtained by purification of the crude product with the use of HPLC. Step 2. A solution of 37 in HOAc-H 2 O (4:1) (5 mL) is stirred under an inert 133 atmosphere at room temperature. The reaction is followed by TLC and when complete, is diluted with EtOAc and washed several times with water and dilute aq. Na^CO,. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired alcohol [38, wherein R = - (CH 2 ) 4 -; R, = R 2 = H; R 8 = F; and R 2 - Br] is obtained by purification of the crude product by use of HPLC. Step 3. A solution, cooled to the temperature of an ice-water bath, containing compound 38 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5% NaHC0 3 , with water and with half-saturated brine. The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated'under reduced pressure to give the cmde product. The desired bromide [39, wherein R = -(CH 2 ) 4 -; R, = R 2 = H; R 8 = F; and R 2 ' = Br] is obtained by purification of the crude product by use of HPLC. Step 4. Sodium hydride (2 mmols) is added to a solution of 7 (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 39 (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH : C1, (3 \ 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [40, wherein R = - (CH,) 4 -; R, = R 2 = H; R 3 = R 4 = R 6 = CH 3 ; R 8 = F; and R 2 , = Br] is obtained by purification of the crude product with the use of HPLC. 134 Example 18: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L,, is the imidazobenzodiazepine nucleus of imidazenil linked through a C-1 methylene group to the linker X and a second ligand, L 2 , is the triazolobenzodiazepine nucleus of alprazolam linked through a C-1 methylene group. A mixture of 8-chloro-l-(3-chloropropyl)l -6-phenyl-4H-s-triazolo[4,3- a][l ,4]benzodiazepine (41 , Hester, Jr., J.B.; et al., J. Med Chem. 1980, 23, 392- 402; 2 mmols), 3-aminopropanol-O-TMS (2 mmols), and KI (2 mmols) in THF (20 mL) is stirrred under an inert atmosphere at RT. The progress of the reaction is monitored by TLC and when the reaction is complete, solvent is removed in vacuo. Water is mixed with the residue and is extracted with CH : C1 2 . The organic extract is washed with half saturated brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound [42, wherein R - -(CH 2 )-; R s '= Cl; R 2 " = R 9 = H] is obtained by purification of the crude product with the use of HPLC. Step 2. A solution of 42 in HOAc-H 2 0 (4: 1 ) (5 mL) is stirred under an inert 135 atmosphere at room temperature. The reaction is followed by TLC and when complete, is diluted with EtOAc and washed several times with water and dilute aq. Na ^ COS. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired alcohol [43, wherein R = - (CH 2 )-; R 8 ' = Cl; R 2 " = R, = H] is obtained by purification of the crude product by use of HPLC. Step 3. A solution, cooled to the temperature of an ice-water bath, containing compound 43 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5% NaHCO 3 , with water and with half-saturated brine. The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired bromide [44, wherein R = -(CH 2 )-; R s ' = Cl; R," = R, = H] is obtained by purification of the crude product by use of HPLC. Step 4. Sodium hydride (2 mmols) is added to a solution of 3 (2 mmols) in dry DMF (5mL) stirred under an inert atmosphere. To this is added a solution of 44 (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 : (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [40, wherein R = - (CH 2 )-; R, = R 2 = R 2 " = H; R 8 = F; R 8 , = Cl and R 2 '= Br] is obtained by purification of the crude product with the use of HPLC. 136 Example 19: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the imidazobenzodiazepine nucleus of imidazenil linked through a C-1 methylene group to the linker X and a second ligand, L,, is the triazolobenzodiazepine nucleus of alprazolam linked through a C-4 methylene group. Sodium hydπde (2 mmols) is added to a solution of 3, (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 12-bromo-l- dodecanol-O-TMS (2 mmol) in dry DMF ( 1 mL) and the resulting mixture is 20 stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back- washed with water. The organic layer is dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound [46, 25 wherein R = -(CH, ) , ; R, = R 2 = H; R 8 = F; and R,. = Br] is obtained by purification of the crude product with the use of HPLC. Step 2. A solution of 46 in HOAc-H 2 O (4: 1 ) (5 mL) is stirred under an inert 137 atmosphere at room temperature. The reaction is followed by TLC and when complete, is diluted with EtOAc and washed several times with water and dilute aq. Na j CO j . The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired alcohol [47, wherein R = - (CH 2 ) ]0 -; R, = R 2 = H; R 8 = F; and R 2 - Br] is obtained by purification of the crude product by use of HPLC. Step 3. A solution, cooled to the temperature of an ice-water bath, containing compound 47 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5% NaHCO , with water and with half- saturated brine. The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired bromide [48, wherein R = -(CH 2 ) 10 -; R, = R 2 = H; R 8 = F; and R 2 '= Br] is obtained by purification of the crude product by use of HPLC. Step 4. Sodium hydride (2 mmols) is added to a solution of 1 1 (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 48 (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [49, wherein R = - (CH 2 ) 10 -; R, - R 2 = R 2 " = H; R 8 - F; R 8 . = Cl and R,*= Br] is obtained by purification of the crude product with the use of HPLC. 138 Example 20: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the imidazopyridine nucleus of zolpidem linked through the carboxamide group to the linker X and a second ligand, L 2 , is the triazolobenzodiazepine nucleus of alprazolam linked through a C-1 methylene group. A mixture of 5 (2 mmols), 4-(N-methylamino)-l-butanol (2 mmol) and ice with 50% aqueous NaOH is mixed vigorously and progress of the reaction is followed by TLC. When the reaction is complete, the mixture is extracted with diethyl ether. The combined ether extracts are washed with water and with half- saturated brine, dried (Na 2 SO ), filtered and concentrated under reduced pressure giving the crude product. The desired compound (50, wherein R = -(CH 2 ) 2 -; R 3 = R 5 = R 6 = CH 3 ) is obtained by purification of the crude product with the use of HPLC. Step 2. A solution, cooled to the temperature of an ice-water bath, containing compound 50 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is 139 removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5%o NaHCO 3 , with water and with half-saturated brine. The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired compound (51, wherein R = -(CH 2 ) 2 -; R 3 = R 5 = R 6 = CH 3 ) is obtained by purification of the crude product by use of HPLC. Step 3. Sodium hydride (2 mmols) is added to a solution of 52, (Hester, Jr., J.B.; et al., J. Med. Chem. 1980, 23, 392-402; 2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 51 (2 mmol) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [53, wherein R = -(CH 2 ) 2 -; R 3 = R 5 = R 6 = CH 3 ; R - Cl; and R 2 " = H) is obtained by chromatography of the crude product using HPLC. Example 21 : Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the imidazopyridine nucleus of zolpidem linked through the carboxamide group to the linker X and a second ligand, L 2 , is the triazolobenzodiazepine nucleus of alprazolam linked through a C-4 methylene group. 140 Step 1. A mixture of 5 (2 mmols), N-methyl-N'-Cbz-l ,6-diaminohexane (2 mmols) and ice with 50% aqueous NaOH is mixed vigorously and progress of the reaction is followed by TLC. When the reaction is complete, the mixture is extracted with diethyl ether. The combined ether extracts are washed with water and with half- saturated brine, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound [54, wherein R = -(CH 2 ) 4 -; R, = R 5 = R 6 = CH 3 ] is obtained by purification of the crude product with the use of HPLC. Step 2. A solution of 54 in ethyl acetate (10 mL) is hydrogenated at atmospheric pressure in the presence of 10% palladium-on-carbon (100 mg) until TLC evidence showed that reaction is complete. The mixture is filtered through Celite and the filter pad is washed thoroughly with ethyl acetate. The combined filtrates are 141 concentrated under reduced pressure to give the crude product. The desired compound [55, wherein R = -(CH 2 ) 4 -; R = R 5 = R 6 = CH 3 ] is obtained by purification of the crude product with the use of HPLC. Step 3. A solution of 55 (1 mmol), 8-chloro-l-methyl-6-phenyl-4H-s-triazolo[4,3- a][l,4]benzodiazepine-4-acetic acid (56; Hester, Jr., J.B.; et al, J. Med. Chem. 1980, 23, 643-7; 1 mmol) and 4-dimethylaminopyridine (10 mg) in CH 2 C1 2 (5 mL) is prepared under argon in a flask equipped with magnetic stirrer and a drying tube. To this solution is added dicyclohexylcarbodiimide (solid, 2.2 mmol). The progress of the reaction is followed by TLC and after the reaction occurs, the reaction solution is quenched in water, aqueous sodium bicarbonate is added and the aqueous mixture is extracted with methylene chloride. The organic layer is washed with aqueous Na 2 CO 3 and with H 2 O, dried (Na j SO , filtered and concentrated under reduced pressure to give the crude product. The desired Formula I compound [57, wherein R = -(CH 2 ) -; R 3 = R 5 = R 6 = CH 3 ; R 8 ' = Cl; and R 2 " = H] is obtained by purification of the crude product with the use of HPLC. Example 22: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the imidazopyridine nucleus of zolpidem linked through the C-4' methylene group to the linker X and a second ligand, L 2 , is the triazolobenzodiazepine nucleus of alprazolam linked through a C-1 methylene group. 142 NaH „ HOAc 7 + BrCH 2 — ^— CH 2 OTMS 5o DMF H-,0 9 Step 1. Sodium hydride (2 mmols) is added to a solution of 7, (2 mmols) in dry DMF (5 mL stirred under an inert atmosphere. To this is added a solution of 3-bromo-l — propanol-O-TMS (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back- washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound [58, wherein R = -(CH 2 )-; R 3 = R 4 = R 6 = CH 3 ] is obtained by purification of the crude product with the use of HPLC. Step 2. A solution of 58 in HOAc-H 2 O (4: 1) (5 mL) is stirred under an inert atmosphere at room temperature. The reaction is followed by TLC and when complete, is diluted with EtOAc and washed several times with water and dilute aq. Na 2 CO 3 . The organic layer is dried (Na 2 S0 4 ), filtered and concentrated under 143 reduced pressure to give the crude product. The desired alcohol [59, wherein R = (CH 2 )-; R 3 = R 4 = R 6 = CH 3 ] is obtained by purification of the crude product by use of HPLC. Step 3. Sodium hydride (2 mmols) is added to a solution of 59, (2 mmols) in dry DMF (5 mL stirred under an inert atmosphere. To this is added a solution of 9 (2 mmols) in dry DMT (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [60, wherein R = - (CH 2 )-; R 3 = R 4 = R 6 = CH 3 ; R 8 , = Cl; and R 2 . = H] is obtained by purification of the crude product with the use of HPLC. Example 23: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L„ is the imidazopyridine nucleus of zolpidem linked through the C-4' methylene group to the linker X and a second ligand, L,, is the 144 triazolobenzodiazepine nucleus of alprazolam linked through a C-4 methylene group. Step 1. Sodium hydride (2 mmols) is added to a solution of 7, (2 mmols) in dry DMF (5 mL) stirred under an inert atmosphere. To this is added a solution of 7-bromo-l- heptanol-O-TMS (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back- washed with water. The organic layer is dried (Na^O , filtered and concentrated under reduced pressure giving the crude product. The desired compound [61 , wherein R = -(CH,) 5 - and R 3 = R 4 = R 6 = CH 3 ] is obtained by purification of the crude product with the use of HPLC. Step 2. A solution of 61 in HOAc-H 2 O (4: 1) (5 mL) is stirred under an inert 145 atmosphere at room temperature. The reaction is followed by TLC and when complete, is diluted with EtOAc and washed several times with water and dilute aq. Na j CO j . The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired alcohol [62, wherein R = - (CH 2 ) 5 -; R 3 = R 4 = R 6 = CHJ is obtained by purification of the crude product by use of HPLC. Step 3. A solution, cooled to the temperature of an ice-water bath, containing compound 62 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5% NaHCO 3 , with water and with half-saturated brine. The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired compound [63, wherein R = -(CH 2 ) 5 -; R 3 = R 5 = R 6 = CH 3 ] is obtained by purification of the crude product by use of HPLC. Step 4. Sodium hydride (2 mmols) is added to a solution of 11, (2 mmols) in dry DMF (5mL) stirred under an inert atmosphere. To this is added a solution of 63 (2 mmols) in dry DMF (1 mL) and the resulting mixture is stirred, warmed and monitored for reaction by TLC. After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL). The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back-washed with water. The organic layer is dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [64, wherein R - - (CH,) 5 -; R 3 = R 4 = R 6 = CH 3 ; R 8 , = Cl; and R 2 " = H] is obtained by purification of the crude product with the use of HPLC. 146 Example 24: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L is the benzodiazepine nucleus of imidazenil linked through the carboxamide group to the linker X and a second ligand, L 2 , is 4- aminobutanoic acid linked through a C-3 oxygen atom. aq NaOH CBr 4 HNCHv "^~ CH 2 OH 65 TPP Step l . A mixture of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[l ,5- a][l,4]benzodiazepine-3-carbonyl chloride (1) (2 mmol), 6-amino-l-hexanol (2 mmols), and ice with 50%> aqueous NaOH is mixed vigorously and progress of the reaction is followed by TLC. When the reaction is complete, the mixture is extracted with diethyl ether. The combined ether extracts are washed with water and with half-saturated brine, dried (Na : SO 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound [65, wherein R = -(CH 2 ) 4 -; R, = H; R 8 = F; and R 2 , = Br] is obtained by purification of the cmde product with the use of HPLC. Step 2. A solution, cooled to the temperature of an ice-water bath, containing 147 compound 65 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred The cooling bath is removed and the solution is stirred at room temperature The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 , washed with aqueous 5% NaHCO,, with water and w ith half-saturated bπne The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product The desired compound [66, wherein R = -(CH 2 ) 4 -, R, = H, R s = F, and R 2 ' = Br] is obtained by purification of the crude product by use of HPLC Step 3 Sodium hydπde (2 mmols) is added to a solution of 4-azιdo-3- hydroxybutanoic acid, ethyl ester (Kobayashi, K , eral , JP 08119935) (2 mmols) in dry DMF (5 m L) stirred under an inert atmosphere To this is added a solution of 66 (2 mmol) in dry DMF (1 mL) and the resulting mixture is stirred, w armed and monitored for progress of the reaction by TLC After the reaction occurs, the mixture is quenched with water (25 mL) and brine (25 mL) The mixture is extracted with CH 2 C1 2 (3 x 20 mL) and the combined organic extracts are back- washed with water The organic layer is dπed (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product The desired compound [6 " wherem R - -(CH 2 ) 4 -, R, = H, R 8 = F, and R 2 - Br] is obtained by purification of the crude product with the use of HPLC Step 4 A solution of 67 (2 mmols) in ethanol (10 mL) is hydrogenated over 5% palladium on carbon When the reaction is complete, as determined by TLC. the reaction mixture is filtered through Celite, the filter pad is washed ith ethanol and the combined filtrates are concentrated under reduced pressure The desired compound [68, wherein R = -(CH 2 ) 4 -, R, = H, R 8 - F and R ' = Br] is obtained b\ purification of the crude product with the use of HPLC 148 Example 25: Preparation of a Formula I compound wherein p is 2, q is 1, and one ligand, L„ is the imidazopyridine nucleus of zolpidem linked through the carboxamide group to the linker X and the second ligand is 4-aminobutanoic acid linked via a 3-aminomethyl group. Step 1. 72 A solution of 5 (2 mmols) in CH 2 C1 2 (5 mL) containing pyridine (0.5 mL w as stirred in an inert atmosphere. To this solution is added 4-aminobutanoic acid, methyl ester (2 mmols) and stirring is continued. The progress of the reaction is monitored by TLC and when the reaction is complete, water and additional CH : C1, are added, the mixture is shaken, the layers are separated and the aqueous layer is further extracted with CH 2 C1 2 . The combined organic extracts are dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired Formula I compound [69, wherein R = -(CH 2 ) 6 -; R 3 = R 5 = R 6 = CH 3 ] is obtained by purification of the crude product with the use of HPLC. Step 2. A solution of 69 (2 mmols)and lithium hydroxide (100 mmols) in methanol (9 mL) and water (3 mL) is stirred at room temperature. The reaction is followed by thin layer chromatography. After the reaction occurs, the pH of the solution is adjusted to 7 by the addition of dilute aq. hydrochloric acid. The solvent is removed 149 by lyophilization and the dry, crude product (70) is used directly in the next reaction. Step 3. A solution containing the crude 70 (1 mmol) and 5-amino-4-(N benzyloxycarbonyl)aminopentanoic acid, methyl ester ( 1 mmol) in methylene chloride (20 mL) is prepared under argon in a flask equipped with magnetic stirrer and drying tube. To this solution is added dicyclohexylcarbodiimide (solid, 1.1 mmols). The course of the reaction is followed by thin layer chromatography while stirring at room temperature. After the reaction occurs, the reaction solution is diluted with ethyl acetate and washed with water and with aqueous Na 2 CO,. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired compound (71) is obtained by purification of the crude product by use of HPLC. Step 4. Ammonium formate (96 mg, 1.5 mmol) and 10%o Pd/C (50 mg) are added to a solution of 71 in methanol (2 mL) and THF (1 mL). The mixture is stirred at room temperature. The reaction is monitored by TLC and after the reaction occurs, the mixture is filtered through Celite and rinsed with ethyl acetate. The filtrate is washed successively with aq. NaHC0 3 and with half- saturated brine, then filtered and concentrated under reduced pressure to give the crude product. The desired Formula I compound [72, wherein R = -(CH 2 ) 2 -; R 3 = H; R 5 = R 6 = CH 3 ] is obtained by purification of the crude product by use of HPLC. Example 26: Preparation of a Formula I compound wherein p is 2, q is 1 , and one ligand, L,, is the triazolobenzodiazepine nucleus of alprazolam linked through a C-1 methylene group to the linker X and the second ligand is 4- aminobutanoic acid linked via a 2-amino group. 150 NH, BOCNHCH 2 CH 2 CHCOOEt BrCH 2 — - DIPEA CH T OTMS CH 2 — @— CH 2 OTMS 73 DMF NH BOCNHCH 2 CH 2 CHCOOEt 74 (BOC) 2 0 Et 3 N CH 2 — ^— CH 2 OH HOAc CH 2 - CH 2 OTMS - I NBOC H,0 NBOC BOCNHCH 2 CH 2 CHCOOEt 76 BOCNHCH 2 CH 2 CHCOOEt 75 Step 1. A solution of 4-(N-BOC-amino)-2-aminobutanoιc acid, ethyl ester (73. Blandon, CM.; et. al., Tetrahedron Lett. 1989, 30, 1401-4; 2 mmol) and 4-bromo- 1-butanol- O-TMS (1 mmol), and diisopropylethylamine (0.2 mL) in DMF (3 mL) is stirred and warmed under an inert atmosphere. The progress of the reaction is followed by TLC and when reaction is complete, the solution is poured into aqueous 5%o NaHC0 3 and the aqueous mixture is extracted with methylene 151 chloride. The organic extract solution is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired compound, 74, is obtained by purification of the crude product by use of HPLC. Step 2. A solution of BOC-anhydride (5 mmol) and triethylamine (0.1 mL) in CH 2 C1 2 (5 mL) is stirred under an inert atmosphere. To this is added a solution of 74 (2 mmol) in CH 2 C1 2 (2 mL) and the resulting solution is stirred. The reaction is followed by TLC and when complete, is quenched by the addition of aqueous Na 2 CO 3 . The mixture is extracted with CH 2 C1 2 the organic extracts are washed with half-saturated saline, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired product, 75, is obtained by purification of the crude product by use of HPLC. Step 3. A solution 75 in HOAc-H 2 0 (4: 1) (5 mL) is stirred under an inert atmosphere at room temperature. The reaction is followed by TLC and when complete, is diluted with EtOAc and washed several times with water and dilute aq. Na 2 CO The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give the crude product. The desired compound, 76, is obtained by purification of the crude product by use of HPLC. Step 4. A solution, cooled to the temperature of an ice-water bath, containing compound 76 (2 mmols), triphenylphosphine (3 mmols), and carbon tetrabromide (4 mmols) in CH 2 C1 2 (10 mL) is prepared and is stirred. The cooling bath is removed and the solution is stirred at room temperature. The progress of the reaction is followed by TLC and after the reaction occurs, the solution is diluted with additional CH 2 C1 2 washed with aqueous 5% NaHC03, with water and with half-saturated brine. The organic layer is separated, dried (Na 2 S0 4 ), filtered and 152 concentrated under reduced pressure to give the crude product. The desired bromo compound, 77, is obtained by purification of the crude product by use of HPLC. Step 5. A mixture of 8-chloro-l-(3-aminopropyl)-6-phenyl-4H-s-triazolo [4,3-] [l,4]benzodiazepine (78, Hester, Jr., J.D.; et al., J. Med. Chem. 1980, 23, 392-402; 2 mmols), 77 (2 mmols), and KI (2 mmols) in THF (20 mL) is stirrred under an inert atmosphere at RT. The progress of the reaction is monitored by TLC and when the reaction is complete, solvent is removed in vacuo. Water is mixed with the residue and is extracted with CH 2 C1 2 . The organic extract is washed with half saturated brine, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure giving the crude product. The desired compound, 79, is obtained by purification of the crude product with the use of HPLC. Step 6. A solution of 79 and trifluoroacetic acid (3 mL) in CH 2 CU (5 mL) is stirred at room temperature. The progress of the reaction is followed by TLC. After the reaction occurs, more CH 2 C is added and the solution is washed with aqueous Na j CO- j and with H 2 O. The organic layer is dried (Na ^ SO , filtered and concentrated under reduced pressure to give the crude product. The desired Formula I compound [80, where R is -(CH,) 2 -; R 2 " = H; R 8 ' = Cl] is obtained by purification of the crude product with the use of HPLC. Example 27: Preparation of a Formula I compound wherein p is 2, q is 1, one ligand, L is the benzodiazepine nucleus of imidazenil linked through the carboxamide group to the linker X and a second ligand, L 2 , is the triazolobenzodiazepine nucleus of triazolam linked through a C-1 methylene group. 153 Step 1. A solution of 6-(2-brornophenyl)-8-fluoro-4H-imidazo[ l ,5- a][l,4]benzodiazepine-3-carbonyl chloride (1, 2 mmols) and 4- bromophenethylamine (2 mmols) in CH 2 C1 2 (10 mL) and pyridine (0.5 mL) is stirred at RT and the progress of the reaction is followed by TLC. When the reaction is complete, water is added and the mixture is extracted with CH 2 C1 2 . The combined organic extracts are washed with water and with half-saturated brine, dried (Na j S04), filtered and concentrated under reduced pressure giving the crude product. The desired compound (81 , wherein R = -CH 2 CH 2 C 6 H 4 -; R, = H; R s = F; R : . = Br) is obtained by purification of the crude product with use of HPLC. Step 2. A solution of 81 (1 mmol), 8-chloro-l-[(N-methyl-N-propargylamino)methyl]- 6-phenyl-4H-s-triazolo[4,3-a][l ,4]benzodiazepine (82, Hester, Jr., J.B.; et al., J. Med Chem. 1980, 23, 392-402; 1 mmol), tetrakis(triphenylphosphine)palladium(0) ( 150 mg), and triethylamine (0.3 mL) in toluene (10 mL) is stirred with copper (I) iodide (20 mg). The mixture is stirred at 100°C and the progress of the reaction is followed by thin layer chromatography (TLC). After the reaction occurs, the mixture is cooled, filtered, and the solvent removed under reduced pressure to give the crude 154 reaction product. The desired compound (structure 83, where R = -CH 2 CH,C ( ,H -; R, = R 2 " = H; R 8 = F; R 2 , = Br; R 8 ' = Cl) is obtained by purification of the crude product with the use of HPLC. 155

Claims: WHAT IS CLAIMED IS: 1. A multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises an agonist, partial agonist, inverse agonist, partial inverse agonist or antagonist of the GABA receptors; and pharmaceutically-acceptable salts thereof. 2. A multibinding compound of formula I: wherein each L is independently a ligand which is an agonist, partial agonist, inverse agonist, partial inverse agonist or antagonist of the GABA receptors; each X is independently a linker; ? is an integer of from 2 to 10; and q is an integer of from 1 to 20; and pharmaceutically-acceptable salts thereof. 3. The multibinding compound of Claim 2 wherein q is less than /?. 4. The multibinding compound of Claim 3 wherein each ligand is independently selected from a compound of formula A-F: 156 wherein: Z a _ j are, independently, an atom or group of atoms serving to connect the ligand, L, to the linker, X; and wherein R, . and R > are, independently, H, alkyl substituted alkyl, cycloalkyl or aryl R 5 _ 6 are, independently, H, alkyl, substituted alkyl, aryl, or halo R g , R 8 ., R 2 . and R 2 , are, independently, H, substituted alkyl, aryl, halo or nitro; and pharmaceutically-acceptable salts thereof. 5. The multibinding compound of Claim 4 wherein the ligand is an agonist of the GABA A receptor. 6. The multibinding compound of Claim 4 wherein the ligand is a partial agonist of the GAB A A receptor. 7. The multibinding compound of Claim 4 wherein the ligand is an antagonist of the GABA A receptor. 8. The multibinding compound of Claim 4 wherein each linker independently has the formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(S), -C(S)0-, -C(S)NR- or a covalent bond where R is as defined below; 157 Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR\ -C(=NR')-NR'-, -NR'-C(=NR')-, -NR'-C(O)-O-, -N=C(X a )-NR\ -P(O)(OR')-O-, -S(O) n CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 9. A multibinding compound of formula II: L'- X'- L' II wherein each L' is independently a ligand comprising an agonist, partial agonist or antagonist of the GABA receptors and X' is a linker; and pharmaceutically-acceptable salts thereof. 10. The multibinding compound of Claim 9 wherein each ligand is independently selected from the group consisting of compounds of formulae A-F 158 B E F Z-.j are, independently, an atom or group of atoms serving to connect the ligand, L, to the linker, X; and wherein R M and R, are, independently, H, alkyl or cycloalkyl; R 5 . 6 are, independently, H, alkyl, or halo; R 8 , Rg,, R 2 . and R 2 .. are, independently, H, halo or nitro; and pharmaceutically- acceptable salts thereof. 11. The multibinding compound of Claim 10 wherein X' has the formula: -X a -Z-(Y a -Z) m -Y°-Z-X a - wherein m is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)0-, -C(O)NR-, -C(S), -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, 159 substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR'-, -C(=NR')-NR\ -NR'-C(=NR')-, -NR'-C(O)-O-, -N=C(X a )-NR'-, -P(O)(OR')-O-, -S(O) n CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 12. A multibinding compound of claim 11 , wherein the ligand is an agonist, partial agonist, inverse agonist or partial inverse agonist of the GABA Λ receptor. 13. The multibinding compound of Claim 12 wherein X" has the formula: -X a -Z-(Y a -Z) m -Y rb D -Z-X - wherein m is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)0-, -C(O)NR-, -C(S), -C(S)0-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene. cycloalkylene, substituted cylcoalkylene, alkenylene. substituted alkenylene, alkynylene, substituted alkynylene. cycloalkenylene, substituted cycloalkenylene. arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR\ -C(=NR')-NR'-, 160 -NR'-C(=NR , -NR'-C(O)-O-, -N= (X a )-NR'-, -P(O)(OR O-, -S(O) n CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 14. A multibinding compound of claim 1 1 , wherein the ligand is an agonist or partial agonist of the GABAb receptor. 15. The multibinding compound of Claim 14 wherein X" has the formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(S), -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene. alkenylene. substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR'-, -C(=XR')-NR'-. -NR'-C(=NR>, -NR'-C(0)-0-, -N=C(X a )-NR'-, -P(0)(OR')-0-, -S(O) n CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 16. A multibinding compound of claim 1 1 wherein the ligand is an antagonist of the GAB A A receptor. 17. The multibinding compound of Claim 4 wherein X" has the formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(S), -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR'-, -C(=NR')-NR'-. -NR'-C(=NR')-, -NR'-C(O)-O-, -N=C(X a )-NR'-, -P(0)(OR')-0-, -S(O)„CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl. alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound comprising 162 from 2 to 10 ligands covalently attached to one or more linkers w herein each of said ligands independently compnses an agonist, partial agonist, erse agonist, partial inverse agonist or antagonist of the G.ABA receptors, and pharmaceutically- acceptable salts thereof. 19. A pharmaceutical composition compnsing a pharmaceuticalK acceptable earner and an effective amount of a multibinding compound of formula 1 ( D p (X) M wherein each L is a ligand comprising an agonist, partial agonist, inverse agonist, partial inverse agonist or antagonist of the GABA receptors. each X is independently a linker; p is an integer of from 2 to 10: and q is an integer of from 1 to 20; and pharmaceutically-acceptable salts thereof 20. The pharmaceutical composition of Claim 1 herein q is less than /> 21. The pharmaceutical composition of Claim 20 w herein each ligand is independently selected from a compound of formula A-F' 163 wherein Z a _, are, independently, an atom or group of atoms serving to connect the ligand, L, to the linker, X; and wherein R M and Rg are, independently, H, alkyl or cycloalkyl; R 5 6 are, independently, H, alkyl, or halo; R 8 , Rg., R 2 , and R 2 „ are, independently, H, halo or nitro; and pharmaceutically- acceptable salts thereof. 22. The pharmaceutical composition of Claim 21 herein the ligand is an agonist or partial agonist of the GABA A receptor. 23. The pharmaceutical composition of Claim 21 w herein the ligand is an agonist of the GABA A receptor. 24. The pharmaceutical composition of Claim 21 wherein the ligand is an antagonist of the GABA A receptor. 25. The pharmaceutical composition of Claim 21 wherein each linker independently has the formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)0-, -C(0)NR-, -C(S), -C(S)0-. -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene. 164 substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR'-, -C(=NR')-NR'-, -NR'-C(=NR')-, -NR'-C(O)-O-, -N=C(X a )-NR'-, -P(O)(OR')-O-, -S(O) n CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 26. A pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of formula II: L'— X'— L' II wherein each L' is independently a ligand comprising an agonist, partial agonist, inverse agonist or antagonist of the GABA receptors; and X' is a linker; and pharmaceutically-acceptable salts thereof. 27. The pharmaceutical composition of Claim 26 wherein each ligand is independently selected from the group compounds of formulas A-F: 165 28. The pharmaceutical composition of Claim 27 wherein X' has the formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(S), -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene. heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -XR'C(O)-, -NR'C(O)NR\ -C(=NR')-NR'-, -NR'-C(=NR')-. -NR'-C(O)-O-, -N=C(X a )-NR'-, -P(O)(OR')-O-, -S(O) n CR'R"-. -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and 166 R, R' and R" at each separate occunence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of formulas A-F. 30. The pharmaceutical composition of Claim 29 wherein X" has the formula: -X a -Z-(Y d -Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X a at each separate occunence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(S), -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occunence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene. alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(0)NR'-, -NR'C(O)-, -NR , C(0)NR'-, -C(=NR')-NR'-, -NR'-C(=NR')-, -NR'-C(O)-0-, -N=C(X )-NR'-, -P(0)(OR')-O-, -S(O) π CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0. 1 or 2: and R, R' and R" at each separate occunence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, 167 substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound as described in claim 1, wherein the ligand is an agonist, partial agonist, inverse agonist or partial inverse agonist of the GABA A receptor. 32. The pharmaceutical composition of Claim 31 wherein X" has the formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)O-, -C(0)NR-, -C(S), -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occunence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -NR'C(O)-, -NR'C(O)NR'-, -C(=NR')-NR'-, -NR'-C(=NR')-, -NR'-C(O)-0-, -N=C(X a )-NR\ -P(0)(OR')-0-, -S(O) n CR'R"-, -S(O) n -NR\ -S-S- and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occunence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 168 33. A pharmaceutical composition comprising a pharmaceutically acceptable earner and an effective amount of a multibinding compound of claim 1 , wherein the ligand is an agonist of the GABAb receptor. 34. The pharmaceutical composition of Claim 33 wherein X" has the formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C(O)-, -C(O)O-, -C(O)NR-, -C(S), -C(S)O-, -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(O)NR'-, -NR'C(O)-, -NR'C(0)NR'-, -C(=NR')-NR'-, -NR'-C(=NR')-, -NR'-C(O)-0-, -N=C(X a )-NR\ -P(0)(OR')-0-, -S(O) π CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occunence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl. substituted alkynyl, aryl, heteroaryl and heterocyclic. 35. A method for treating neurological disorders mediated by the GABA receptors in a patient, the method comprising administering to a patient having a neurological disorder a pharmaceutical composition comprising a pharmaceutically- 169 acceptable earner and a therapeutically-effective amount of a multibinding compound compnsing from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises an agonist, partial agonist, partial inverse agonist or antagonist of the GABA receptors, and pharmaceutically-acceptable salts thereof 36 A method for enhancing GABA-induced chloride currents at the GABA receptor/ionophore complex in a mammal which comprises administering to said mammal a pharmaceutical composition having anticonvulsant or anxiolvtic activity which comprises a pharmaceutically-acceptable earner and a therapeutically-effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently compnses an agonist, partial agonist or antagonist of the GABA receptors, and pharmaceutically-acceptable salts thereof, wherein the compound is present in the composition an amount effecm e for preventing or ameliorating convulsant seizures or anxiety in the mammal to w hich it is administered 37 A method for treating convulsant seizures m a mammal which compnses administenng to the mammal a pharmaceutical composition having anticonvulsant or anxiolytic activity which compnses a pharmaceutically-acceptable earner and a therapeutically-effective amount of a multibinding compound compnsmg from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently compnses an agonist, partial agonist or antagonist of the GABA receptors, and pharmaceutically-acceptable salts thereof, wherein the compound is present in the composition in an amount effectiv e for preventing or ameliorating convulsant seizures or anxiety in the mammal to hich it is administered 38 A method for producing sedation or hypnosis in a mammal which 170 comprises administering to the mammal a pharmaceutical composition having sedative or hypnotic activity which comprises a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises an agonist, partial agonist or antagonist of the GABA receptors; and pharmaceutically-acceptable salts thereof, wherein the compound is present in said composition in an amount effective for preventing or ameliorating convulsant seizures or anxiety in the mammal to which it is administered. 39. A method for producing retrograde amnesia in a mammal which comprises administering to the mammal a pharmaceutical composition having amnesia producing activity which comprises a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises an agonist, partial agonist or antagonist of the GABA receptors; and pharmaceutically-acceptable salts thereof, wherein the compound is present in said composition in an amount effective for preventing or ameliorating convulsant seizures or anxiety in the mammal to which it is administered. 171 40. A method for treating anxiety in a mammal which comprises administering to the mammal a pharmaceutical composition having anticonvulsant or anxiolytic activity which comprises a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises an agonist, partial agonist or antagonist of the GABA receptors; and pharmaceutically-acceptable salts thereof, wherein the compound is present in said composition in an amount effective for preventing or ameliorating convulsant seizures or anxiety in the mammal to which it is administered. 41. A method for treating emesis, which comprises administering to a mammal suffering from or susceptible to emesis an effective amount of a pharmaceutical composition which comprises a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises an agonist, partial agonist or antagonist of the GABA B receptors; and pharmaceutically-acceptable salts thereof, wherein the compound is present in said composition in an amount effective for preventing or ameliorating emesis in the mammal to which it is administered. 42. A method for identifying multimeric ligand compounds possessing multibinding properties which method comprises: (a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) 172 with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands, and (d) assaying the multimenc ligand compounds produced in the library prepared in (c) above to identify multimenc ligand compounds possessing multibinding properties 43 A method for identifying multimenc ligand compounds possessing multibinding properties which method compnses (a) identifying a library of ligands wherem each ligand contains at least one reactn e functionality, (b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand, (c) prepanng a multimenc ligand compound library by combining at least two stoichiometnc equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands, and (d) assaying the multimenc ligand compounds produced in the library prepared in (c) above to identify multimenc ligand compounds possessing multibinding properties 44 The method according to Claim 42 or 43 wherem the preparation of the multimenc ligand compound library is achieved by either the sequential or concunent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b) 45 The method according to Claim 44 wherem the multimenc ligand compounds compnsing the multimenc ligand compound library are dimenc 173 46. The method according to Claim 45 wherein the dimeric ligand compounds comprising the dimeric ligand compound library are heteromeric. 47. The method according to Claim 46 wherein the heteromeric ligand compound library is prepared by sequential addition of a first and second ligand. 48. The method according to Claim 44 or 45 wherein, prior to procedure (d), each member of the multimeric ligand compound library is isolated from the library. 49. The method according to Claim 46 wherein each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS). 50. The method according to Claim 42 or 43 wherein the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and/or polarizability and amphiphilic linkers. 51. The method according to Claim 50 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups. 52. The method according to Claim 51 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100A. 53. The method according to Claim 42 or 43 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands. 174 54. The method according to Claim 53 wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof wherein the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand. 55. The method according to Claim 42 or 43 wherein the multimeric ligand compound library comprises homomeric ligand compounds. 56. The method according to Claim 42 or 43 wherein the multimeric ligand compound library comprises heteromeric ligand compounds. 57. A library of multimeric ligand compounds which may possess multivalent properties which library is prepared by the method comprising: (a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands. 58. A library of multimeric ligand compounds which may possess multivalent properties which library is prepared by the method comprising: 175 (a) identifying a library of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands. 59. The library according to Claim 57 or 58 wherein the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and/or polarizability and amphiphilic linkers. 60. The library according to Claim 59 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups. 61. The library according to Claim 60 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100A. 62. The library according to Claim 57 or 58 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands. 63. The library according to Claim 62 wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof 176 wherein the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand. 64. The library according to Claim 58 or 59 wherein the multimeric ligand compound library comprises homomeric ligand compounds. 65. The library according to Claim 57 or 58 wherein the multimeric ligand compound library comprises heteromeric ligand compounds. 66. An iterative method for identifying multimeric ligand compounds possessing multibinding properties which method comprises: (a) preparing a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which target a receptor with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; (b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multibinding properties; (c) repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties; (d) evaluating what molecular constraints imparted or are consistent with imparting multibinding properties to the multimeric compound or compounds found in the first iteration recited in (a)- (c) above; 177 (e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibinding properties to the multimeric compound or compounds found in said first iteration; (f) evaluating what molecular constraints imparted or are consistent with imparting enhanced multibinding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above; (g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints. 67. The method according to Claim 66 wherein steps (e) and (f) are repeated from 2-50 times. 68. The method according to Claim 66 wherein steps (e) and (f) are repeated from 5-50 times. 178

Inventors: BEATTIE DAVID T, GRIFFIN JOHN H, MORAN EDMUND J, BEATTIE, DAVID, T., GRIFFIN, JOHN, H., MORAN, EDMUND, J.
Applicants: ADVANCED MEDICINE INC, BEATTIE DAVID T, GRIFFIN JOHN H, MORAN EDMUND J, ADVANCED MEDICINE, INC., BEATTIE, DAVID, T., GRIFFIN, JOHN, H., MORAN, EDMUND, J.
Application year: 1999
Main classification: A61K
IPC codes: A61K31, A61K38, A61K45, A61K47, A61P9, A61P11, A61P13, A61P15, A61P17, A61P21, A61P25, A61P27, A61P43, C07B61, C07C215, C07C217, C07C237, C07C271, C07C311, C07C323, C07D207, C07D209, C07D211, C07D213, C07D215, C07D221, C07D223, C07D235, C07D239, C07D241, C07D249, C07D257, C07D263, C07D265, C07D277, C07D295, C07D401, C07D403, C07D413, C07D417, C07D471, C07D487, C07D495, C07D519, C07K1, C07K2, C07K4, C07K7, C07K16, C40B20, G01N33, G01N37