MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5HT2 RECEPTORS

Abstract: Disclosed are multibinding compounds which are agonists, partial agonists, inverse agonists or antagonists of the 5HT2 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 or antagonist of the 5HT2 receptors. The multibinding compounds of this invention are useful for the prophylaxis and treatment of various neurological disorders such as depression, anxiety, epilepsy, psychosis, schizophrenia, Alzheimer's disease, drug addiction, sleep and eating disorders, migraine and pain.

Description: MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5HT 2 RECEPTORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 60/088,466 filed on June 8, 1998 and U.S. Provisional Application No. 60/092,938 filed on July 15, 1998, both of which are incorporated by reference herein in their entirety. BACKGROUND OF THE INVENTION This invention relates to novel multibinding compounds (agents) that are agonists, partial agonists, inverse agonists and antagonists for the 5HT 2 receptors, and to pharmaceutical compositions comprising such compounds. The compounds are useful medications for the prophylaxis and treatment of various neurological disorders, such as schizophrenia and the like. References The following publications are cited in this application as superscript numbers: 1 Hrib et al.. J. Med. Chem.. 39:4044-4057 (1996) 2 Goren and Levin, Pharmacotherapy. 18(6):1183-1194 3 Szewczak et al.. J. Pharm. Exp. Ther.. 274:1404-1413 (1995)) 4 Roth et al., Pharmacol. Ther. 79(3):231-257 (1998) All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety. State of the Art Schizophrenia is a complex and devastating disease, with a worldwide lifetime prevalence of almost 1% of the general population. The disease exhibits a variety of symptoms, and it is not known whether the many symptoms of schizophrenia are the product of a single or a multiple disease entity- Symptoms are divided into positive and negative syndromes. The positive symptoms of schizophrenia include hallucinations and delusions. The negative symptoms such as apathy, lack of motivation, and social withdrawal, can persist after the positive symptoms have been alleviated and hinder the patient's complete return to society. Compounds that inhibit postsynaptic dopaminergic neurotransmission have been effective in treating schizophrenia. However, most of these agents are typical, i.e., they show some propensity for the development of extrapvramidal side effects (EPS), either acutely (dystonia, pseudo-Parkinsonism) or on chronic administration (Tardive Diskinesia (TD)). In addition, few of these agents have shown efficacy against the negative symptoms. In the last several years, atypical antipsychotic drugs, which are more efficacious and which lack the typical neurological side effects of the typical antipsychotic drugs, have been developed. No universally accepted definition of an atypical antipsychotic agent exists, but criteria include some of the following: serotonergic and dopaminergic antagonism with greater antagonism at serotonergic receptors; superior efficacy compared with conventional agents; efficacy against the negative symptoms of schizophrenia, absence of EPS at clinically effective doses; absence of TD; and no elevation of serum prolactin levels. Currently, clozapine, risperidone (Janssen Pharmaceutica NV), olanzapine (Eli Lilly), iloperidone (Hoescht Marion Roussel, Inc.), quetiapine (Zeneca Group p.c), iloperidone and sertindole (H Lundbeck A/S) are atypical drugs which have been developed. These compounds are generally dibenzothiazepines or piperidinyl benzoxazoles. All have broad pharmacological profiles with affinity for serotonergic, dopaminergic, muscarinic, histamine and α- 1 adrenergic receptors 2 . Atypical antipsyochotic drugs are distinguished by their interactions at various serotonergic (5HT) and dopaminergic (D) receptors. Since the discovery of the clinical antipsychotic activity of chlorpromazine in the 1950's, the pharmacological antagonism of central dopamine receptors remains the only proven method of treating schizophrenia. There is convincing evidence that the efficacy of these agents in treating psychotic symptoms results from dopamine receptor antagonism in the mesolimbic/mesocorical dopamine system. Unfortunately, chronic treatment with pure dopamine antagonists, while effectively treating some of the symptoms of schizophrenia, can also result in the onset of Parkinson-like EPS and a progressively increasing risk of TD. These phenomena are thought to be a consequence of the blockade of dopamine receptors in the corpus striatum, the terminal region of the nigrostriatal dopamine track. There is an increasing body of evidence that suggests that agents that antagonize serotonergic receptors, in particular, the 5HT 2A receptors, in the brain along with dopaminergic receptors may have an improved ratio of therapeutic effects to EPS. For example, the antipsychotic agents clozapine and risperidone have high affinities for the serotonergic receptors in addition to weak or moderate affinity for dopamine receptors 3 . Thus, diversity rather than selectivity appears to be the prominent receptor feature that is common to all atypical antipsychotic drugs. Serotonin (5-hydroxytryptamine; 5-HT) is a major neurotransmitter involved in a large number of CNS processes, including the regulation of feeding behavior, aggression, mood, perception, pain and anxiety. In the periphery, 5-HT is important for regulating vascular and nonvascular smooth muscle contraction, platelet aggregation, uterine smooth muscle growth, and gastrointestinal functioning. To mediate these functions, a family of receptors, divided into seven main types and including at least 15 different receptors, has evolved. All, except the 5HT 3 receptors, are typical G-protein coupled receptors (GPCRs) containing transmembrane spanning domains. Antipsychotic drugs are mainly active at the 5HT 2A and 5HT 2C receptors (collectively referred to herein as 5HT 2 receptors unless otherwise specified), 5HT 6 and/or 5HT 7 receptors, are used in the treatment of many disorders, including schizophrenia and depression. 5HT 2A receptors are expressed in large amounts in various cortical regions, with lower levels of expression in the basal ganglia and hippocampus. 5HT 2A receptors also occur in the platelets, vascular smooth muscle, uterine smooth muscle, and other tissues. 5HT 2C receptors are found in the choroid plexus as well as many other brain regions, including the cortex, basal ganglia, hippocampus and hypothalmus 4 . As discussed above, the current agents available as antipsychotics include the benzothiazepines and the piperinyl benzisoxazoles. Many of them have poor bioavailability and a high incidence of side effects. It would be advantageous to provide agents useful as agonists, partial agonists, inverse agonists and antagonists of the 5HT 2 receptors which have higher bioavailability and which can be modified to control their side effect profiles. It would also be advantageous to provide compounds with increased potency, increased selectivity for the 5HT 2 receptors, and controlled efficacy (i.e., antagonism at the 5HT 2 receptors versus the D2 dopamine receptors). The present invention provides such agents. SUMMARY OF THE INVENTION This invention is directed to novel multibinding compounds (agents) that are agonists, partial agonists, inverse agonists, and antagonists of the 5HT 2 receptors. The multibinding compounds of this invention are useful in the treatment and prevention of disorders mediated by the 5HT 2 receptors. In particular, 5-HT 2A agonists can be used to treat sleep and eating disorders. 5-HT 2A antagonists can be used to treat depression, anxiety, epilepsy, psychosis, schizophrenia, Alzheimer's disease, drug addiction, and sleep and eating disorders. 5-HT 2C agonists can be used to treat sleep and eating disorders. 5-HT 2C antagonists can be used to treat anorexia, eating disorders, epilepsy, sleep disorders, psychosis, schizophrenia, Alzheimer's disease, migraine, pain, and drug addiction. 5-HT 2B agonists can be used to treat sleep and eating disorders. 5- HT 2B antagonists can be used to treat migraine, pain, eating disorders, and sleep disorders. The compounds are preferably 5HT-, antagonists, which may also have affinity for the D2 receptors. When used to treat schizophrenia, and where the compounds have affinity for D2 receptors, it is preferred that the ratio of affinity for the 5HT, receptors versus the D2 receptors is at least 1 : 1, more preferably, at least 10: 1, and most preferably, at least 50: 1. 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 or antagonist or the 5HT, receptors, and pharmaceutically-acceptable salts thereof. In another of its composition aspects, this invention provides a multibinding compound of formula I: (LUX), wherein each L is independently a ligand comprising an agonist, partial agonist, inverse agonist or antagonist of the 5HT 2 receptors; each X is independently a linker; p is an integer of from 2 to 10; and q is an integer of from to 20; and pharmaceutically-acceptable salts thereof. Preferably, q is less than/? in the multibinding compounds of this invention. Preferably, when the ligand is an antagonist of the 5HT 2 X receptors, each ligand, L, in the multibinding compound of formula I is independently selected from a compound of formula IA, IB or IC, which are modeled after the structural formulae for Zotepine, Risperidone and MDL-100907, also shown below: R i speπdone MDL-100907 IC wherein A is H, alkyl or a direct link to the linker; M, .10 are, independently, H or a direct link to the linker, wherein only one of A or M, . , 0 is a link to the linker; and analogs thereof. Suitable analogs include alkylated, acylated, aminated, thiolated, hydroxylated, amidated, carboxylated, phosphorylated, sulfonated, and halogenated analogs thereof. The following formulas show examples of synthons of zotepine, risperidone and MDL-100907, which can be used to prepare the ligands and/or which represent examples of suitable ligands, depending on the definitions of A-D: -8- wherein A is H, alkyl, substituted alkyl, or a direct link to the linker, B is A, halo, OA or COOA Examples of these synthons are illustrated below: -10a-- -10b- -11- 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 comprising an agonist, partial agonist, inverse agonist or antagonist of the 5HT 2 receptors and X' is a linker; and pharmaceutically-acceptable salts thereof. Preferably, in the multibinding compound of formula II, each ligand, L', is independently selected from the group consisting of ligands of the formulae 1A-C above 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) n CR'R"-, -S(O) n -NR'-, -S-S- and a covalent bond; where n is 0, 1 or 2; and -12- 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 5HT 2 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 of formula I or II. The multibinding compounds of this invention are effective agonists, partial agonists, inverse agonists or antagonists of the 5HT 2 receptors, which are involved in a number of disorders. Accordingly, in one of its method aspects, this invention provides a method for treating various disorders mediated by the 5HT, receptors. Such disorders include various neurological diseases such as schizophrenia. When used to treat neurological disorders, for example, the method involves 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, inverse agonist or antagonist of the 5HT 2 receptors; and pharmaceutically-acceptable salts thereof. -13- 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 5HT 2 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, hydrophihcity or hydrophobicity, amphiphihcity, acidity, basicity and polarizability 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 5HT 2 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 5HT 2 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 5HT 2 receptors which method comprises: (a) identifying a ligand or a mixture of ligands which bind to the 5HT 2 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) -14- 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 5HT 2 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 heteromeric or multimeric compounds are prepared. Concurrent addition of the ligands occurs when at least a portion of the multimer comounds prepared are homomultimeric compounds. -15- 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 the 5HT 2 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 the 5HT 2 receptors which may possess multivalent properties which library is prepared by the method comprising: (a) identifying a library of ligands which bind to the 5HT 2 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. -16- 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 polarizability and/or polarization 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 lOOA. 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, pseudohahdes isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates 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 heteromeric (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 5HT 2 receptors. Specifically, this method aspect is directed to a method for identifying multimeric ligand compounds possessing multibinding properties with respect to the 5HT 2 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 -17- mixture of ligands which target the 5HT 2 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 5HT 2 receptor antagonists and synthons useful for preparing the compounds of the present invention. -18- Figures 2A-2F illustrate examples of dimer structures including two 5HT 2A receptor antagonists. Figure 3 illustrates examples of multibinding compounds comprising 2 ligands attached in different forms to a linker. Figure 4 illustrates examples of multibinding compounds comprising 3 ligands attached in different forms to a linker. Figure 5 illustrates examples of multibinding compounds comprising 4 ligands attached in different forms to a linker. Figure 6 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 5HT 2 receptors, pharmaceutical compositions containing such compounds and methods for disorders mediated by 5HT 2 receptors, preferably 5HT 2A receptors. 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, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, w-propyl, wo-propyl, «-butyl, iso- butyl, «-hexyl, w-decyl, tetradecyl, and the like. -19- 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, -S0 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 3 )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 -20- 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, «-propoxy, iso-pvopoxy, «-butoxy. tert-butoxy, sec-butoxy, w-pentoxy, «-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 ), -propylene-iso-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- -21- alkyl and include, by way of example, methylenethiomethoxy (-CH 2 SCH 3 ), ethylenethiomethoxy (-CH 2 CH 2 SCH 3 ), «-propylene-tso-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 ), n-propenyl (-CH 2 CH=CH 2 ), iso-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, -22- 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. -23- 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,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 2 -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. -24- 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)O-, 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, - -25- 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. -26- 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, -SO 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, -S0 2 -aryl and -S0 2 -heteroaryl. The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo. -27- 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 or 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. -28- 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 -substituted 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, imidazohdine, imidazohne, 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. -29- 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 stericaUy 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 -30- 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(wo-propyl) amine, tri(«-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N- -31- 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 and, 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. -32- 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 or antagonist of the 5HT 2 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 5HT 2 -33- 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 bioavailibity, 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 -34- 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) exhibit 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: -35- 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 50 's (i.e., the concentrations that produce 50% of the maximum response for the ligand interacting with the two distinct ligand binding sites (receptors)). -36- The term "ligand binding site" denotes the site on the 5HT 2 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. However, in one embodiment, the ligand(s) merely bind to a ligand binding site and do not have agonistic or antagonistic activity. 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 opposite 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. -37- 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 5HT 2 receptors in general, and those disease states which have been found to be usefully treated by -38- a specific multibinding compound of our invention. Such disease states include, by way of example only, the following: 5-HT 2A agonists can be used to treat sleep and eating disorders. 5-HT 2A antagonists can be used to treat depression, anxiety, epilepsy, psychosis, schizophrenia, Alzheimer's disease, drug addiction, sleep and eating disorders. 5-HT 2C agonists can be used to treat sleep and eating disorders. 5-HT 2C antagonists can be used to treat anorexia, eating disorders, epilepsy, sleep disorders, psychosis, schizophrenia, Alzheimer's disease, migraine, pain, and drug addiction. 5-HT 2B agonists can be used to treat sleep and eating disorders. 5-HT 2B antagonists can be used to treat migraine, pain, eating disorders, and sleep disorders. 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, -39- 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 4 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. 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 -40- 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 5HT 2 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 -41- 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 urea 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. Suitable linkers and ligands are discussed more fully below. -42- 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 -43- 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". By controlling the hydrophihcity/hydrophobicity, the ability of the compounds to cross the blood/brain barrier can be controlled. This can be important when one wishes to maximize or minimize CNS effects. Examples of molecular structures in which the above bonding patterns could be employed as components of the linker are shown below. -44- 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. Numerous strategies are known to those skilled in the art of molecular design and can be used for preparing compounds of this invention. It is to be noted that 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. -45- 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. 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, hydrophihcity, linker flexibility, antigenicity, stability, and the like. For example, the introduction of one or more -46- poly(ethylene glycol) (PEG) groups onto or into the linker enhances the hydrophihcity 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 hydrophihcity 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 incorporated 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 .-47-. 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 glycosphingohpid 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. -48- 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 incorporating 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 counterparts 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, include deprotectation 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. -49- 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 hgands 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 3, where each shaded -50- 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 4 and 5 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 (a branched construct analogous to the isomers of butane — w-butyl, zso-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 6 where, as before, the -51- shaded circles represent ligands. 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 X and variants thereof. All of the above variations are intended to be within the scope of the invention defined by the formula (L) p (X) q . 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 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, -52- 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: « 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. -53- In one embodiment of this invention, the linker (i.e., X, X' or X") is selected 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(O)-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 ) 7 -C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O (CH 2 ) g -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 ) I0 -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 ) 12 -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 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 ) 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 ) 2 -NH- where Z is 4-biphenyl -54- Linker -HN-(CH 2 ) 2 -NH-C(O)-Z-C(O)-NH-(CH 2 ) 2 -NH- where Z is 5-(n-butyloxy)-l,3-phenyl -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 8 -tra«5-(CH=CH)-C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 2 -CH(NH-C(O)-(CH 2 ) I2 -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 ) 2 -NH-C(O)-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 3 -C(O)-NH-(CH 2 ) 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 ) 2 -NH-C(O)-(CH 2 )-N+((CH 2 ) 9 -CH 3 )(CH 2 -C(O)-NH-(CH 2 ) 2 -NH 2 )- (CH 2 )-C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 )-N((CH 2 ) 9 -CH 3 )-(CH 2 )-C(O)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 2 -NH-C(O)-(CH 2 ) 3 -C(O)-NH- (CH 2 ) 2 -C(O)-NH-(CH 2 ) 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-hydroxy-l,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 -55- 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 or antagonist of the 5HT 2 receptors and which can be covalently linked to a linker can be used as a ligand to prepare the compounds described herein. Such ligands are well known to those of skill in the art. When used to treat psychosis, for example, to treat schizophrenia, the most preferred ligands are antagonists of the 5HT 2A receptors. Examples of 5HT 2 ligands which can be used as ligands to prepare the compounds of the present invention include clozapine, seroquel, risperidone, olanzapine, ziprasidone, quetiapine, olanzapine, sertinole, iloperidone and analogs thereof. Analogs (for these and other known compounds which bind to the 5HT 2 receptors) which can be used include alkylated, acylated, carboxylated, amidated, sulfonated, phosphorylated, aminated, hydroxylated, thiolated, and halogenated derivatives. Various ergot derivatives, such as methysergide, have 5HT 2 antagonist activity, and are effective in the prophylaxis of migraine. These ergot derivatives can be used as ligands. ORG 5222 (Organon) combines dopamine Dl and D2 antagonist properties with antagonism at a variety of serotonin receptor sub-types, and can also be used as a ligand. Iloperidone, a mixed D2/5HT2 antagonist with preferential affinity for 5HT2A receptors in humans, has good activity against both positive and negative symptoms of schizophrenia. -56- Preferred ligands, L, in the multibinding compounds are independently selected from a compound of formula I A, IB or IC: -57- I C and analogs thereof, wherein A is H, alkyl or a direct link to the linker; M [.I0 are, independently, H or a direct link to the linker, wherein only one of A or M,. 10 is a link to the linker; and analogs thereof. Suitable analogs include alkylated, acylated, aminated, thiolated, hydroxylated, amidated, carboxylated, phosphorylated, sulfonated, and halogenated analogs thereof. Ligands of formula IA, IB and IC (and the precursors and analogs 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 IA, IB, IC or related compounds suitable for use in this invention: Julius et al., Proc. Natl. Acad. Sci., USA, 87:928-932 (1990) Kapur, Psychopharmacol., 124:35-39 (1996) Kehne et al., J. Pharmacol, and Exp. Ther. τ 277(2):968-981 (1996) -58- Kinon and Lieberman, Psychopharmacol., 124:2-34 (1996) Leysen et al., Psychopharmacol., 112:S40-S54 (1993) T.ieherman et a1. ; Biol. Psychiatry, 44:1099-1 1 17 (1998) Pariich et al.. Phychopharmacology, 124:107-116 (1996) Richelson, J. Clin. Psychiatry, 57(supp. 1 1):4-11 (1996) Roth et al, Pharmacol. Ther., 79(3):231-257 (1998) Schaus and Bymaster, Ann. Reports in Med. Chem., 33: 1 -10 (1998) Strupczewski et al., J. Med. Chem., 28(6)761-769 (1985) Ueda et al., Chem. Pharm. Bull., 2fi(10):3058- 070 (1978) PCT WO 91/18602 by Merrell Dow EP 0 208 235 Bl to Merrell Dow EP 0 531 410 Bl to Merrell Dow 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. The following formulas show examples of suitable ligands and/or synthons of suitable ligands, depending on the definitions of A-D. -59- -60- wherein: A is H, alkyl, substituted alkyl, or a direct link to the linker, B is A, halo, OA or COOA C is H. or Examples of t hese synthons are illustrated below: -61- -61a- -61b- -62- 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. Any compound which is an agonist, partial agonist, inverse agonist or antagonist of the 5HT 2 receptors, preferably antagonists of the 5HT 2A receptors, can be used as a ligand in this invention. As discussed above, numerous such receptor agonists, partial agonists, 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. 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 above provide numerous examples of suitably functionalized agonists, partial agonists and -63- antagonists of the 5HT 2 receptors, and intermediates thereof, which may be used as ligands in this invention. The ligands can be covalently attached to the linker through any available position on the ligands, provided that when the ligands are attached to the linker, at least one of the ligands retains its ability to bind to the 5HT 2 receptors. Certain sites of attachment of the linker to the ligand are preferred based on known structure-activity relationships. 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. 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 nucleophihc group, can be covalently linked to a linker precursor containing a nucleophihc group or a leaving group, using conventional reagents and conditions. Other methods are well known to those of skill in the art for coupling molecules such as the ligands described herein with the linker molecules described herein. 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 nucleophihc 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 nucleophihc 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, dusopropylethylamine and the like. Nucleophihc substition reactions are typically conducted in an inert diluent, such as tetrahydrofuran, NN-dimethylformamide, NN-dimethylacetamide, acetone, 2- -64- 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 nucleophihc groups and a 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 hgand 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 -65- 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 ester 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 precursors 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. -66- 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)propylcarboiimide (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), 1 -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. -67- 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 dusopropylethylamine 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) -68- 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 of 5HT 2 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 -69- 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, hydrophihcity) 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 -70- 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 heteromeric 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. -71- ϊ, inker Selection In the library of linkers employed to generate the library of candidate multibinding compounds, the selection of linkers employed in this library of hnkers takes into consideration the following factors: Valency: In most instances the library of linkers 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 encompass 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 -72- 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, hydrophihcity, amphiphihcity, 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 « 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 -73- 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 -74- 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. -75- 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 advantage 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 dicarboxyhc acids, disulfonylhahdes, dialdehydes, diketones, dihalides, diisocyanates,diamines, diols, mixtures of carboxylic acids, sulfonylhahdes, 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 Chemisties First Reactive Group Second Reactive Group Linkage hydroxyl isocyanate urethane -76- amine epoxide β -hydroxy amine 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 urea Exemplary linkers include the following linkers identified as X-1 through X- as set forth below: -77- -77a- -77b- -77c- X-50 X-61 X-62 -77d- X-71 X-72 X-73 X-77 X-78 -77e- -78- -78a- v -123 78c- X-136 X-141 -79- X-178 X-179 X-180 -80a- -80c- X-286 X-287 " <? •/V< -ΛΛ CH. H 2 N ^ NH 2 X-298 X-299 -80d- Chiral X-306 X-320 -81a- X-333 X-335 X-336 X-337 HO X-344 -81b- X-361 X-362 X-366 X-367 X-375 X-374 -81d- ^ H 3 .0. O OH HO' - Λ 'OH X-379 X-380 X-381 X-382 X-383 X-385 Dithiols X-386 X-387 X-388 SH X-390 -82- X-392 X-394 ■417 -83- 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. 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. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, -84- gelatin, calcium silicate, microcrystaUine 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. 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, -85- 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 incoφorated 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 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 -86- 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, microcrystaUine 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 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: -87- 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 MicrocrystaUine 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 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 Exampk.5 Capsules, each containing 40 mg of medicament are made as follows: Quantity Ingredient (mg/capsule) -88- 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 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 (11%) MicrocrystaUine 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 microcrystaUine cellulose and sodium carboxymethyl cellulose in water. The -89- 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 rr lug 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. 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 1 - 10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g 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. -90- 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). Utility The multibinding compounds of this invention are agonists, partial agonists, inverse agonists or antagonists of the 5HT 2 receptors, preferably antagonists of the 5HT 2A receptors, which are known to mediate numerous disorders. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of various disorders, in particular, neurological disorders, mediated by 5HT 2 receptors. Examples of central nervous disorders which can be treated using the compounds described herein include schizophrenia, depression, anxiety, disturbance of memory and dementia. In particular, 5-HT 2A agonists can be used to treat sleep and eating disorders. 5-HT 2A antagonists can be used to treat depression, anxiety, epilepsy, psychosis, schizophrenia, Alzheimer's disease, drug addiction, sleep and eating disorders. 5- HT 2C agonists can be used to treat sleep and eating disorders. 5-HT 2C antagonists can be used to treat anorexia, eating disorders, epilepsy, sleep disorders, psychosis, schizophrenia, Alzheimer's disease, migraine, pain, and drug addiction. 5-HT 2B agonists can be used to treat sleep and eating disorders. 5-HT 2B antagonists can be used to treat migraine, pain, eating disorders, and sleep disorders. -91- 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 puφose 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, schizophrenia, 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. -92- Schizophrenia Conventional therapy with typical antipsyochotics such as thorazine and haloperidol (D2 antagonists) decrease positive symptoms, but have no effect on negative symptoms. They also are associated with side effects such as parkinsonism ("Thorazine shuffle") and tardive dyskinesia. These side effects can be minimized by administering compounds which are more selective toward 5HT 2A receptors, by co-administering these compounds with compounds which are more selective toward 5HT 2A receptors, or by preparing compounds including one more ligands which are selective toward 5HT 2A receptors and which also include ligands which are selective D2 antagonists, for example, thorazine or haloperidol and analogs thereof. In one embodiment, the compounds include one or more ligands which are D2 selective and one or more ligands which are 5HT 2A selective. This combination of ligands is useful in treating the positive and negative effects. In another embodiment, the compounds include combinations of 5HT 2 ligands and ligands which are serotonin 1(A or D) receptor antagonists. The effects of the 5HT 2 ligands on terminal 5-HT are significantly enhanced by coadministration of the 5-HT, (A or D) antagonists. Further, by combining the 5HT 2 ligands and ligands which are serotonin 1(A or D) receptor antagonists, the antidepressants may be more potent and take effect faster. Examples of such compounds include compounds which combine 5HT 2 ligands and paroxetine (Paxil), sertraline (Zoloft) or fluoxetine (Prozac). Migraine As discussed above, 5-HT 2c and 5-HT 2B antagonists are useful for treating migraine headaches. Examples of useful compounds include various ergot derivatives, such as methysergide, which have 5HT2-antagonist activity and are effective in the prophylaxis of migraine. -93- Combinatorial Chemistry 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. 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 lOOA. The ligand or mixture of ligands can have reactive functionality at different -94- sites on the ligands. The reactive functionality can be, for example, carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohahdes, 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 5HT 2 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 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. -95- 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 = NN-dimethylformamide 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 ANALYTICAL EXAMPLES Example 1 : In vitro Radioligand binding studies. Receptor binding assays for the 5HT 2 and D2 receptors are performed on rat membrane preparations. In general, after rapid decapitation and dissection of the appropriate brain tissue, crude membrane pellets are prepared by homogenization and centrifugation. Aliquots of membrane homogenate are added to test tubes containing buffer, radioligand, and various concentrations of inhibitor. Nonspecific binding is determined using an excess of the specified inhibitor for the receptor of interest. Following the appropriate incubation conditions, the reactions are -96- terminated by separating the membrane bound from free radioligand by rapid filtration over Whatman GF/C filters. Bound radioligand is quantified by scintillation spectroscopy. The percent inhibition of radioligand binding at each test concentration is calculated, and an IC 50 is determined by log-probit analysis. Example 2: In vivo assays predicting efficacy Apomoφhine-induced climbing. Groups of eight drug naive CD-I male mice weighing 20-30 grams are used. At the time of testing, the mice are individually placed in wire mesh stick cages and are allowed at least one hour to habituate. Animals are treated in a dosave golume of 10 ml/kg with test compounds at various pretreatment times before apomoφhine challenge. Apomoφhine Hcl is subcutaneously injected at 1.5 mg/kg in a dosage volume of 10 ml/kg. Mice are scored for climbing behavior at 10, 20 and 30 minutes after apomoφhine challenge, according to the scale: 0: no climbing; 1 : two paws on the wall, rearing; 2: four paws on the wall, full climb. The maximum climbing score for each animal is 6 and for each group (n = 8 animals) is 48. The total score of the control group is set at 100%; drug treatment group effects are normalized against this group, and an ED 50 is calculated by linear regression analysis. 5HT induced head twitch. Groups of eight drug naive CD-I male mice weighing 180-200 grams are used. Sixty minutes before scoring head twitch behavior, 5HTP is administered at a dose of 240 mg/kg i.p. Test compounds are either dissolved in distilled water or suspended in distilled water with the addition of a drop fo Tween 80, and 30 minutes after the 5HTP injection, are administered i.p. Control groups receive the appropriate vehicle. Each animal is placed individually in a clear plastic cage, and 60 minutes after 5HTP administration, is observed for head twitch response in the presence of white noise. The number of head twitches per anumal is recorded over a 10 minute interval, and the total is summed for each group. The percentage _-97-_ change from control for each drug treatment is calculated, and ED 50 values for each drug are calculated by linear regression analysis. Inhibition of intracranial self stimulation. Male Wistar rats, weighing 300-350 g, are housed individually and surgically implanted with unilateral bipolar stainless steel electrodes. The rats are anesthitized with 50 mg/kg i.p. sodium pentobarbital with supplemental anesthesia administered to maintain deep surgical anasthesia as required, and positioned in a stereotaxic instrument, where an electode is aimed at the medial forehead bundle at th elevel of the lateral preoptic nucleus according to the atlas of Paxinos and Watson. Tthe electrode assembly is affixed to the cranium with stainless steel screws and bone cement. After at least a 5 day recovery period, the subjects are trained to bar press for electrical stimulation in a standard operant behavior box. The stimulus, a train of biphasic square wave pulses, is generated by a square wave signal generator. The stimulation pararmaters are pulse duration of 0.5 msec with 2.5 msec between each pulse pair; pulse frequency is varied between 16 and 30 pulses per second to achieve maximal responding. Animals are trained twice per week with each session lasting 30 minutes. Baseline performance criteria of at least 2000 responses/30 minutes with no more than a 5% change from the average of the last three training sessions are used. Drug testing occurs over 2 consecutive days. On a first day, rats are evaluated for conformance to baseline responding parameters over a 30 minute period. On the second day, test compound or vehicle is administered i.p. to groups of four rats and evaluated 60 minutes later for its effects on bar pressing behavior over a 30 minute test session. The change in response number compared with the previous day's control rate is determined for each animal to adjust for between subject differences in responding. ED 50 s for the inhibition of bar pressing activity -98- are determined using linear regression analysis of the percent change from the control for each subject. Pole climb avoidance. Individually housed, adult male Long Evans rats are trained to avoid a foot shock accompanied by a warning tone by climbing onto a smooth stainless steel pole suspended from the ceiling of the test cage. The test cages consist of behavioral chambers that re housed in dimly lit, sound attenuating chambers to mask extraneous noises. Each cage contains a grid floor for the administration of constant current scrambled shock, a 2.8 kHz Sonalert and a light. A stainless steel pole suspended from the center of the ceiling is connected to a microswitch that is activated by a weight of 200 g. The smooth surface of the pole prevents rats form avoiding grid floor shock by remaining on the pole. Control of the experimental contingencies and recording of responses are accomplished with a minicomputer. All the trials of pole climb avoidance commence with the onset of light and tone stimuli. Four seconds later, 1.5 mA of scrambled shock is delivered to the grid floor. The tone, light and shock are terminated simultaneously 30 seconds after the beginning of a trial in the absence of a response. A pole climb response within the first 4 seconds of each trial is recorded as an avoidance response, and a response after shock onset is recorded as an escape response. Experimental compounds are administered i.p. to groups of six to nine rats in a volume of 1 ml/kg, 60 minutes before the test session. ED 50 values for inhibition of avoidance responding and for inhibition of escape responding (escape failure) are calculated by linear regression of the percentage change from control for each subject. Example 3: In vivo assays predicting extrapyramidal side effect liability. Apomoφhine-induced stereotypy: -99- Groups of 6-10 drug naive male Wistar rats weighing 125-200 g are treated i.p. in a dose volume of 10 ml/kg with test compounds 50 minutes before apomoφhine challence and placed in individual clear plastic cages. Apomoφhine Hcl is administered at a dose of 1.5 mg/kg s.c. in a dose volume of 1 ml/kg. A 10 second observation period for the presence of stereotyped behavior, i.e., licking, sniffing or gnawing, is measured 10 minutes after apomoφhine challenge (60 minutes after the compound is administered(. The percentage inhibition of the drug is determined by the number of animals not demonstrating stereotypy in each group compared with the control group. The ED 50 value for antagonism of stereotypy is calculated by probit analysis. Catalepsy: Groups of 6-10 drug naive male Wistar rats weighting 150-300 g are used as subjects. Compounds are aministered i.p. in a dose volume of 10 ml/kg. Catalepsy is assessed at various times after drug treatment. Animals are individually placed in white, translucent plastic boxes with a wooden dowel mounted horizontally 10 cm from the floor and 4 cm from one end of the box. After 2 minutes of acclimation to the box, the animal's forepaws are gently placed on the wooden bar. The subject is considered cataleptic if it remains in this position for 60 seconds. The percentage catalepsy is determined by the number of cataleptic animals in each treatment group compared with the control group. The ED 50 value for catalepsy is calculated by probit analysis. Example 4: In vivo assays for predicting anxioly tic/negative symptom efficacy: Elevated plus maze: Drug naive male Wistar rats weighing 200-225 g are housed in pairs under standard laboratory conditions for 5 days before testing. The elevated plus maze (X-maze) consists of 4 arms positioned parallel to and 50 cm above the floor. Two arms are enclosed by 30 cm high walls; the other two arms are open. The four -100- arms are arranged in a plus shape, such that the two arms of each type are opposite each other. One day before testing, the animals are familiarized with the laboratory test room for 30 minutes and handled for 5 minutes by the experimenter. On the day of testing, rats are randomly assigned to groups of eight and indivually placed in the center of the maze, facing one of the enclosed arms. During a 5 minute period, the following measurements are made by a trained observer: the number of entries into, the time spent in the open and enclosed arms, and the total number of arm entries. Experimental compounds are dissolved in distilled water or suspended in distilled water with 1 drop of Tween 80. All compounds are administered i.p. in a volume of 1 ml/kg 30 minutes before the test session. Drug treatment groups are then compared with the vehicle group. Social interaction in rats: Drug naive male Wistar rats weighing 200-275 g are housed in pairs for 5 days before testing. Measurement of social interaction is conducted in a plexiglass test cage located in a room with moderate illumination. For 2 days before testing, pairs of rats that have been housed together are placed in a test cage for 8 minutes to habituate them to the environment. On test day, rats are treated with test compounds or vehicle and matched according to weight (to within 10 g) with an unfamiliar animal to form groups of six pairs. Each unfamiliar pair is placed in a test cage for 5 minutes, and their social interaction and total activity are observed and recorded via closed circuit television. The duration in second of the following behaviors is recorded as social interaction: sniffing, climbing over or under, mutual grooming, genital investigation and following or walking around partner. Aggressive behavior is not recorded. Total activity is measured as the frequency of rearing responses (front legs off floor) plus the number of body lengths traveled. Compounds are administered i.p. to the groups either 30 minutes or 60 minutes before the test session. Drug treatment groups are then compared with the vehicle group. -101- Another useful assay is light and sound pre-pulse inhibition, which is described, for example, in Padich et al., Psychopharmacology, 124: 107-116 (1996), the contents of which are hereby incoφorated by reference. Preparative Examples Preparation 1: 8-chloro-10-[2-(N-methylamino)ethoxy]dibenzo[b,fjthiepin, 60, (Synthon A) and the functionalized derivatives 61 and 62. A. Sodium hydride (5 mmol) is added to a solution of 8- chlorodibenzo[b,fjthiepin-10(l lH)-one, 57 prepared as described in Chem. Pharm. Bull., 1975, 23, 2223, (5 mmol) in toluene (25 mL) at 65°. After 1 hour, 2-[N-(tert- butoxycarbonyl-N-methylamino)ethyl chloride, 58, prepared as described in J. Med. Chem., 1998, 41, 5429, (10 mmol) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is cooled and it is added to water. The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford 8-chloro-10-[2-(N-methyl-N-tert- butoxycarbonylamino)ethoxy] dibenzo [b, f] thiepin 59. B. The above compound 59 (1 mmol) is dissolved in CH 2 C1 2 (10 mL) and TFA (5 mL) is added. The progress of the reaction is monitored by tic. When it is complete, the solvents are removed under vacuum and the residue is dissolved in CH 2 C1 2 . The solution washed with dilute NaOH, then the organic phase is washed, dried and evaporated, and the residue is chromatographed to afford 8-chloro-10-[2- (N-methylamino)ethoxy]dibenzo[b,fJthiepin 60. C. The above compound 60 (2 mmol) is dissolved in DMF (20 mL) and methyl bromoacetate (2 mmol) and K 2 CO 3 (0.5g) are added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford 8-chloro-10-[2-N- -102- (methoxycarbonylmethyl)(N-methylamino)ethoxy]dibenzo[b,fJthiepin, 61 , in which R is methyl. D. The above compound 61 ( 1 mmol) is dissolved in THF (10 mL) and a solution of LiOH, H 2 O (2 mmol) in water (10 mL) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water; the pH is adjusted to 7 by addition of dilute HCl, and the solution is extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford 8-chloro-10-[2-N-(carboxymethyl)(N- methylamino)ethoxy]dibenzo[b,f]thiepin, 61, in which R is H. E. The compound 60 (2 mmol) is dissolved in DMF (10 mL) and K 2 CO 3 (0.5g), KI (50 mg) and 1,3-dibromopropane (2 mmol) are added. The mixture is heated to 60° and the progress of the reaction is monitored by tic. When it is complete, the solution is cooled and it is added to water. The aqueous solution is extracted with EtOAc. The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford 10-[2-N-(3-bromopropyl)(N- methylamino)ethoxy]-8-chlorodibenzo[b,fJthiepin, 62. F. Using the above procedures, but employing in Steps C and E different bromoalkyl esters or dibromoalkanes, products analogous to 61 and 62 are obtained. The chemistry is shown below: -103- -NH ^A -104- Preparation 2: 8-hydroxy-10-[2-(N,N- dimethyIamino)ethoxy]dibenzo[b,fJthiepin, (Synthon B) 66, and 8-(3- bromomethylbenzyloxy)-10-(2-N,N-dimethylaminoethoxy)dibenzo[b,fJthiepin, 68. A. 8-Hydroxydibenzo[b,fJthiepin-10(l lH)-one 63, prepared as described in Coll. Czech. Chem. Commun., 1975, 23, 2223, (5 mmol) is dissolved in DMF (50 mL) and imidazole (10 mmol) and tert-butylchlorodiphenylsilane (6 mmol) are added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford 8-(tert- butyldiphenylsilyloxy)dibenzo[b,f]thiepin-10(l lH)-one, 64. B. Using the conditions of Preparation IA, but employing 2-chloro-N,N- dimethylethylamine in place of 2-[N-(tert-butoxycarbonyl-N-methylamino)ethyl chloride, there is obtained the compound 8-(tert-butyldiphenylsilyloxy)-10-(2-N,N- dimethylaminoethoxy)dibenzo[b,f]thiepin, 65. C. The above compound 65 (1 mmol) is dissolved in THF (10 mL) and IM Bu 4 NF in THF (20 mL) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford 8-hydroxy-10-(2-N,N-dimethylaminoethoxy)dibenzo[b,f]thiepin 66. D. Using the conditions of Preparation IC, the above compound 66 is reacted with one molar equivalent of l,3-di(bromomethyl)benzene 67, to afford 8- (3-bromomethylbenzyloxy)-10-(2-N,N-dimethylaminoethoxy)dibenzo[b,f]thiepin, 68, stored as the hydrobromide salt. E. Using the above procedure, but employing different dibromo compounds in place of l,3-di(bromomethyl)benzene, the products analogous to 68 are obtained. -105- The chemistry is shown below: -106- Preparation 3: 10-[2-(N,N-dimethylamino)ethoxy]dibenzo[b,fjthiepin-8- carboxylic acid (Synthon C, 71) and the 2-aminoethylamide thereof, 72. A. Using the conditions of Preparation 1 A, but employing 2-chloro-N,N- dimethylethylamine in place of 2-[N-(tert-butoxycarbonyl-N-methylamino)ethyl chloride, there is obtained the compound 2-dimethylaminoethyl 10-[2-(N,N- dimethylamino)ethoxy]dibenzo[b,f]thiepin-8-carboxylate, 70. B. Using the hydrolysis conditions of Preparation ID, the above compound 70 is converted into 10-[2-(N,N-dimethylamino)ethoxy]dibenzo[b,f]thiepin 8- carboxylic acid, 71. C. The above compound 71 (2 mmol) is dissolved in CH 2 C1, (10 mL) and SOCl 2 (0.5 mL) and DMF (0.1 mL) are added. After 1 hour, the solvents are removed under vacuum to afford the acid chloride of 71. D. The above described acid chloride is dissolved in MeCN (10 ML) and ethylene diamine (1 mL) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the compound 72. E. Using the above procedure, but employing different diamino compounds in place of ethylenediamine, the amide products analogous to 72 are obtained. The chemistry is shown below: -107- -108- Preparation 4: 3-[4-[l-(6-bromohexyl)piperidinyl]]-6-fluorobenz[d]isoxazoIe, 74. A. Using the conditions of Preparation IE, 3-(4-piperidinyl)-6- fluorobenz[d]isoxazole, (Synthon D) 73, prepared as described in J. Med. Chem., 1985, 28, 761, (2 mmol) is reacted with 1,6-dibromohexane to afford the compound 74. B. Using the above conditions, but substituting different dibromo compounds for 1,6-dibromohexane, the corresponding bromoalkyl compounds are obtained. The chemistry is shown below: -109- Synthon D 73 74 -110- Preparation 5: 3-[4-(N-methylpiperidinyl)]-6-hydroxybenz[d]isoxazole, (Synthon E) 82, and 6-(3-carboxypropyloxy)-3-[(4-(N- methylpiperidinylbenz[d]isoxazole, 83, in which R is H. A. Using the silylation conditions of Preparation 2A, 4-bromo-l,3- dihydroxybenzene 75 is converted into 4-bromo-l,3-di(tert- butyldiphenylsilyloxy)benzene, 76. B. The above compound 76 (2 mmol) is dissolved in THF (20 mL) under an inert atmosphere, and IN n-BuLi in hexane (2 mL) is added. After 1 hour, the solution is cooled to -78° and a solution of 4-(N-methoxy-N-methylcarbonyl)-N- methylpiperidine, 78, prepared as described in WO9850346, (2 mmol) in THF (10 mL) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford 4-[2,4- di(tert-butyldiphenylsilyloxy)benzoyl] -N-methylpiperidine 79. C. Using the desilylation conditions of Preparation 2C, the above compound 79 is converted into 4-(2,4-dihydroxyoxybenzoyl)-N-methylpiperidine 80. D. To a solution of hydroxylamine hydrochloride (5 mmol) in EtOH (25 mL) is added IM NaOH (5 mL) and the compound 80 (1 mmol). The solution is heated at reflux and the progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the compound 82. E. The above compound 82 (1 mmol) is dissolved in DMF (lOmL) and methyl 4-bromobutyrate (3 mmol), K 2 CO 3 (0.5 g) and KI (50 mg)are added. The mixture is heated to 60° and the progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The -i norganic phase is washed, dried and evaporated, and the residue is chromatographed to afford the compound 83 in which R is methyl. F. Using the hydrolysis procedure of Preparation ID, the above ester is converted into the corresponding carboxylic acid 83 in which R is H. G. Using the procedures E and F above, different bromoaikanoic esters can be reacted with the compound 82 to afford the ethers corresponding to compound 83. The chemistry is shown below: -112- -113- Preparation 6: 6-(5-bromo-3-oxapentyloxy)benzo[d]isoxazole, 85. A. Using the alkylation procedure of Preparation 5E, 6- hydroxybenzo[d]isoxazole (Synthon F, 84) prepared as described in Aust. J. Chem., 1977, 30, 1847, is reacted with l,5-dibromo-3-oxapentane to afford the compound 85. B. Using the above procedure different dibromo compounds can be reacted with the compound 84 to afford the ethers analogous to compound 85. The chemistry is shown below: -114- Synthon F 84 85 -1 15- Preparation 7: (R) α-(2,3-dimethoxyphenyl)-4-piperidinemethanol, (Synthon G, 92) and (R) l-(3-carboxypropyl)-α-(2,3-dimethoxyphenyI)-4- piperidinemethanol, 93. A. 4-(2,3-dimethoxybenzoyl)-l-(tert-butoxycarbonyl)piperidine 86, prepared as described in European Patent 531410 (5 mmol) is dissolved in MeOH (50 mL) and NaBH 4 (10 mmol) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to dilute HCl and extracted with EtOAc. The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford α-(2,3-dimethoxyphenyl)-l-tert-butoxycarbonyl-4- piperidinemethanol, 87. B. Using a procedure similar to that described in European Patent 531410, the above compound 87 (2 mmol) is dissolved in DMF (20 mL) and S-(+) α- methoxyphenylacetic acid 88 (2 mmol), dicyclohexylcarbodiimide (2 mmol) and 4- dimethylaminopyridine (50 mg) are added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated to afford a residue containing the diastereomeric esters 89. The individual diastereomers are separated by chromatography, so affording the diastereomer 90. This compound (1 mmol) is dissolved in MeOH (20 mL) and a solution of K 2 CO 3 (4 mmol) in water (5 mL) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford (R ) α-(2,3- dimethoxyphenyl)- 1 -tert-butoxycarbonyl-4-piperidinemethanol 91. C. Using the deprotection procedure of Preparation IB, the above compound 91 is converted into Synthon G, 92. —116— D. Using the alkylation procedure of Preparation IE, the compound 92 is reacted with methyl 4-bromobutyrate,and the resulting ester is hydrolyzed using the procedure of Preparation ID, to afford the carboxylic acid 93. E. Using procedures C and D above, the amine 92 is reacted with different bromoaikanoic acid esters to afford the corresponding carboxylic acids analogous to 93. The chemistry is shown below: -116a- -117- Preparation 8: (R ) α-(2-methoxy-3-hydroxyphenyl)-l-[2-(4- fluorophenyl)ethyI]-4-piperidinemethanol, (Synthon H, 101) and α-[3-(4- bromobutoxy)-2-methoxyphenyl]-l-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol, 102. A. Using the silylation procedure of Preparation 2 A, 3-hydroxy-2- methoxybromobenzene 94, prepared as described in Tetrahedron Letters, 1984, 36, 3955, is converted into 3-(tert-butyldiphenylsilyloxy)-2methoxybromobenzene, 95. B. The above compound 95 (2 mmol) is dissolved in THF (20 mL) under an inert atmosphere, and IN n-BuLi in hexane (2 mL) is added. After 1 hour, the solution is cooled to -78° and a solution l-[2-(4-fluorophenyl)ethyl-4- formylpiperidine 97, prepared as described in European Patent 531410, (2 mmol) is added. After 1 hour, the solution is added to water and extracted with CH,C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford α-[3-(tert-butyldiphenylsilyloxy)-2-methoxyphenyl]- 1 -[2-(4- fluorophenyl)ethyl]-4-piperidinemethanol 98. C. Using the procedure of Preparation 7B, the compound 98 is converted into the ester 99 by reaction with S-(+) α-methoxyphenylacetic acid 88. The silyl group is removed using the procedure of Preparation 2C, and the resulting mixture 100 is separated into the individual diastereomers by chromatography, and the ester group is hydrolyzed to afford Synthon H, 101. D. Using the alkylation procedure of Preparation 5E, the phenol 101 is reacted with 1,4-dibromobutane to afford the compound 102. E. Using the above procedure, the compound 101 is reacted with different dialkylating agents to afford the ether compounds analogous to 102. The chemistry is shown below: -118- -119- Preparation 9: (R) α-(2,3-dimethoxyphenyl) l-[2-(4-carboxyphenyl)ethyl]-4- piperidinemethanol, (Synthon 1, 106) and the derived 4-aminophenyI amide 107 A. Using the alkylation procedure of Preparation IE, (R) α-(2,3- dimethoxyphenyl)-4-piperidinemethanol 103, prepared as described in European Patent 531410, is reacted with 2-(4-carbomethoxyphenyl)ethyl bromide 104, prepared as described in J. Med. Chem., 1993, 36, 1880, to afford (R ) α-(2,3- dimethoxyphenyl)-l-[2-(4-carbomethoxyphenyl)ethyl]-4-piperidinemethanol 105. B. Using the hydrolysis procedure of Preparation ID, the ester 105 is converted into the carboxylic acid 106, (Synthon I). C. The above acid 106 (1 mmol) is dissolved in DMF (20 mL) and dicyclohexylcarbodumide (1 mmol) and 1 ,4-diaminobenzene (1 mmol) are added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the amide 107. D. Using the above procedure, but employing different diamines in place of 1,4-diaminobenzene, the aminoamides analogous to 107 are obtained. The chemistry is shown below: -120- -121- Preparation 10: (R ) 4-bromo-l-(2,3-dimethoxyphenyl)butanol, 112, and (R ) l-(2,3-dimethxoyphenyι)-4-mercaptobutanol 113. A. Using the procedure of Preparation 5B, 2-3-dimethoxyphenyllifhiurn 108, prepared as described in J. Amer. Chem. Soα, 1997, 119, 1476, and 4-bromo-N- methoxy-N-methylbutanamide 109, prepared as described in Syn. Comm., 1990, 20, 1105, are reacted together to afford l-bromo-3-(2,3-dimethoxybenzoyl)propane 110. B. Using the reduction procedure of Preparation 7 A, the ketone 110 is converted into 4-bromo-l-(2,3-dimethoxyphenyl)butanol, 111. C. Using the resolution procedure of Preparation 7B, the racemic carbinol 111 is converted into the enantiomer 112. D. The compound 112 (2 mmol) is dissolved in EtOH (50 mL) and thiourea (5 mmol) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated. The residue is redissolved in EtOH (25 mL) and tetramethylene pentamine (5 mmol) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the thiol 113. E. Using the above procedures, but employing in Step A different bromo compounds, there are obtained different analogs of compounds 112 and 113. The chemistry is shown below: 122 -123- Preparation 11: (R) 5-methylamino-l-(2,3-dimethoxyphenyl)pentanol 115. A. Using the procedures of Preparation 10A-C, and substituting 5-bromo-N- lnethoxy-N-methylpentanamide, prepared as described in J. Amer. Chem. Soc, 1997, 1 19, 1476 for 4-bromo-N-methoxy-N-methylbutanamide 109 in Step A, there is obtained (R) 5-bromo-l-(2,3-dimethoxyphenyl)pentanol, 114. B. The above compound 114 (5 mmol) is dissolved in EtOH (50 mL) and methylamine (5 mL of a 50% solution in EtOH) is added. The mixture is heated under reflux. The progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the compound 115. The chemistry is shown below: -124- 114 115 -125- Preparation 12: l-bromo-6-(2,3-dimethoxyphenoxy)hexane, 118. A. Using the alkylation procedure of Preparation 5E, 2,3-dimethoxyphenol 116 is reacted with 1,5-dibromopentane to afford the compound 118. B. Using the above procedure, but employing different dibromo compounds in place of 117 there are obtained the alkylated compounds analogous to 118. The chemistry is shown below: -126- -127- Preparation 13: (R) α-(2,3-dimethoxyphenyl) l-(carboxymethyl)-4-piperidine- methanol, 120. Using the alkylation procedure of Preparation IC, (R) α-(2.3- 5 dimethoxyphenyl)-4-piperidinemethanol 92 is reacted with methyl bromoacetate. The ester product so obtained is hydrolyzed , using the conditions of Preparation ID, to afford the carboxylic acid 120. The chemistry is shown below: 10 BrCH 2 COOCH 3 Synthon G 92 119 -128- Preparation 14 (R) α-(2,3-dimethoxyphenyl) l-[2-[4-(2- aminoethylaminocarboπyl)phenyl]ethyl]-4-piperidiπemethanol, 122. A. (R) α-(2,3-Dimethoxyphenyl) l-[2-(4-carboxyphenyl)ethyl]-4- piperidinemethanol 106 (2 mmol) is dissolved in DMF (20 mL) and dicyclohexylcarbodumide (2 mmol) and ethylenediamine (5 mmol) are added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the amide 122. B. Using the above conditions, but employing different diamines in place of ethylenediamine, there are obtained the corresponding amides analogous to 122. The chemistry is shown below: -129- -130- Example 1: Dimer Type A-A. Reaction between 8-chloro-10-[2-(N- methylamino)ethoxy]dibenzo[b,f]thiepin, 60 and 10-[2-N-(3-bromopropyl)(N- methylamino)ethoxy]-8-chlorodibenzo[b,f]thiepin, 62, to afford the dimeric amine 123. A. The amine 60 (1 mmol) and the bromo compound 62 (1 mmol) are heated at reflux in EtOH (15 mL). The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the compound 123. B. Using the above procedure, but employing in place of 62 the different bromo compounds described in Preparation IF, there are obtained the corresponding compounds 13. The chemistry is shown below: -131- -132- Example 2: Dimer type A-G: reaction between 8-chloro-10-[2-N- (carboxymethyl)(N-methylamino)ethoxy]dibenzo[b,f]thiepin, 61 and (R) α- (2,3-dimethoxyphenyl)-4-piperidinemethanol, (Synthon G, 92) to afford the dimeric amide 124. A. The carboxylic acid 61 (1 mmol) and the amine 92 (1 mmol) are dissolved in DMF (10 mL) and dicyclohexylcarbodumide (2 mmol) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the dimeric amide 124. B. Using the above procedure, but employing in place of 61 different carboxylic acids, prepared as described in Preparation IF, the corresponding dimers 19 are obtained. The chemistry is shown below: -133- -134- Example 3: Dimer type B-B. Reaction between 8-hydroxy-10-[2-(N,N- dimethylamino)ethoxy]dibenzo[b,f]thiepin, (Synthon B) 66, 8-(3- bromomethylbenzyloxy)-10-(2-N,N-dimethylaminoethoxy)dibenzo[b,f]thiepin, 68. A. The phenol 66 (1 mmol) and the benzylic bromide 68 ( 1 mmol) are dissolved in DMF (15 mL) and K 2 CO 3 ( 0.5 g) is added. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the dimeric ether 125. B. Using the above procedure, but employing in place of 68 different bromo compounds, prepared as described in Preparation 2E, the corresponding dimers 22 are obtained. The chemistry is shown below: -135- Synthon B 66 68 125 -136- Example 4: Dimer type B-C. Reaction between 8-(3-bromomethyIbenzyloxy)- 10-(2-N,N-dimethylaminoethoxy)dibenzo[b,f]thiepin, 68 and the amine 72 to afford the dimeric amine 126. A. The bromo compound 68 (1 mmol) and the amine 72 (1 mmol) are dissolved in EtOH (20 mL) and dusopropylethylamine (2 mmol) is added. The mixture is heated at reflex and the progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the dimer 126. B. Using the above procedure, but employing in place of 68 and 72 different reactants, prepared as described in Preparations 2E and 3E, the corresponding dimers 23 are obtained. The chemistry is shown below: -137- -138- Example 5: Dimer types C-C, I-I and C-I. Reaction between 10-[2-(N,N- dimethylamino)ethoxy]dibenzo[b,f]thiepin-8-carboxylic acid (Synthon C, 71) (R) α-(2,3-dimethoxyphenyl) l-[2-(4-carboxyphenyl)ethyl]-4- piperidinemethanol, (Synthon 1, 106) and 1,5-pentanediamine 127, to afford the dimeric amides 128, 129 and 130. A. The carboxylic acid 71 (1 mmol), the carboxylic acid 106 (1 mmol) and 1,5-pentanediamine 127 (0.5 mmol) and dicyclohexylcarbodumide (2 mmol) are dissolved in DMF (10 mL). The progress of the reaction is .lonitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the dimeric amides 128, 129 and 130. B. Using the above procedure, but employing different diamines in place of 127, there are obtained the corresponding dimeric compounds 30, 35 and 56. The chemistry is shown below: -139- -140- Example 6: Dimer type D-D. Reaction between 3-[4-[l-(6- bromohexyι)piperidinyl]]-6-fluorobenz[d] isoxazole, 74 and 3-(4-piperidinyl)- 6-fluorobenz[d]isoxazole, (Synthon D) 73 to afford the dimer 131. A. The bromo compound 74 (1 mmol) and the amine 73 (1 mmol) are heated at reflux in EtOH (20 mL) containing dusopropylethylamine (5 mmol) The progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the dimeric compound 131. B. Using the above procedure, but employing different bromo compounds, prepared as described in Preparation 4C in place of 74, the corresponding dimers 36 are obtained. The chemistry is shown below: -141- -142- Example 7: Dimer type D-I. Reaction between , 3-(4-piperidinyI)-6- fluorobenz[d] isoxazole, (Synthon D) 73 and (R) α-(2,3-dimethoxyphenyl) l-[2- (4-carboxyphenyl)ethyl]-4-piperidinemethanol, (Synthon 1, 106) to afford the dimeric amide 132. The amine 73 (1 mmol), the carboxylic acid 106 (1 mmol) and dicyclohexylcarbodumide (1 mmol) are dissolved in DMF (20 mL). The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the dimeric compound 132. The chemistry is shown below: -143- -144- Example 8: Dimer type E-E. Reaction between 3-[(4-(N-methylpiperidinyl)]-6- hydroxybenz[d] isoxazole, (Synthon E) 82 and (Z)-l,4-dibromo-2-butene 133 to afford the symmetrical dimer 134. A. The phenol 82 ( 1 mmol), (Z)-l,4-dibromo-2-butene 133 (0.5 mmol) and dusopropylethylamine (1 mmol) are dissolved in MeCN (10 mL) the mixture is heated at reflux and the progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the dimeric compound 134. B. Using the above procedure, but employing different dibromo compounds in place of (Z)-l,4-dibromo-2-butene, there are obtained the corresponding dimers 42. The chemistry is shown below: -145- -146- Example 9: Dimer type E-I. Reaction between 6-(3-carboxypropoxy)-3-[(4-(N- methylpiperidinylbenz[d] isoxazole, 83 and the amine 107, to afford the amide dimer 135. A. The carboxylic acid 83, the amine 107 (1 mmol) and dicyclohexylcarbodumide (1 mmol) are dissolved in DMF. The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The organic phase is washed, dried and evaporated, and the residue is chromatographed to afford the dimeric amide 115. B. Using the above procedure but employing in place of the amine 107 different amines, prepared as described in Preparation 9D, the corresponding compounds 46 are obtained. The chemistry is shown below: -147- 135 -148- Example 10: Dimer type A-F. Reaction between 8-chloro-10-[2-(N- methylamino)ethoxy]dibenzo[b,f]thiepin, 60, (Synthon A) and 6-(5-bromo-3- oxapentyloxy)benzo[d]isoxazole, 85, to afford the amine-linked dimer 136. A. The amine 60 (1 mmol) and the bromo compound 85 (1 mmol) and dusopropylethylamine (2 mmol) are heated at reflux in EtOH (20 mL) The progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the dimeric compound 136. B. Using the above procedure, but employing in place of 60 and 85, analogues thereof the preparations of which are described respectively in Preparations IF and 6B, different compounds of structure 18 are obtained. The chemistry is shown below: -149- -150- Example 11: Dimer type F-H. Reaction between 6-hydroxybenzo[d]isoxazole (Synthon F, 84) and α-[3-(4-bromobutoxy)-2-methoxyphenyI]-l-[2-(4- fluorophenyl)ethyl]-4-piperidinemethanol, 102, to afford the ether-linked dimer 137. A. The phenol 84 (1 mmol), the bromo compound 102 (1 mmol), K 2 CO 3 (250 mg) and KI (25 mg) are dissolved in DMF (10 mL) The mixture is heated at 60° and the progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CHC 1 -,. The extract is dried and evaporated, and the residue is chromatographed to afford the dimer 137. B. Using the above procedure, but employing in place of the bromo compound 102, different analogs, obtained according to the procedures of Preparation 8E, different compounds of structure 49 are obtained. The chemistry is shown below: -151- -152- Example 12: Dimer type G-G. Reaction between (R) α-(2,3- dimethoxyphenyl)-4-piperidinemethanoI, (Synthon G, 92) and (R) l-(3- carboxypropyl)-α-(2,3-dimethoxyphenyl)-4-piperidinemethanol, 93, to afford the amide-linked dimer 138. A. The amine 92 (1 mmol), the carboxylic acid 93 (1 mmol) and dicyclohexylcarbodumide (1 mmol) are dissolved in DMF (5 mL). The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the amide 138. B. Using the above procedure, but employing in place of the carboxylic acid 93, different analogs, obtained as described in Preparation 7E, different compounds 1 are obtained. The chemistry is shown below: -153- -154- Example 13: Dimer type G-C. Reaction between (R) l-(3-carboxypropyI)-α- (2,3-dimethoxyphenyl)-4-piperidinemethanoI, 93 and the amine 72, to afford the amide-linked dimer 139. A. The carboxylic acid 93 (1 mmol), the amine 72 (1 mmol) and dicyclohexylcarbodumide (1 mmol) are dissolved in DMF (10 mL). The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the compound 139. B. Using the above procedure, but employing in place of 93 and 72, different analogs thereof, obtained according to the procedures of Preparations 7E and 3F respectively, there are obtained the corresponding compounds 33. The chemistry is shown below: -155- -156- Example 14: Dimer type H-H. Reaction between (R) α-(2-methoxy-3- hydroxyphenyI)-l-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, (Synthon H, 101) and (R) α-[3-(4-bromobutoxy)-2-methoxyphenyl]-l-[2-(4- fluorophenyl)ethyl]-4-piperidinemethanoI, 102 to afford the ether-linked dimer 141. A. The phenol 101 (1 mmol) and the bromo compound 102 (1 mmol) are heated at reflux in EtOH (10 mL) containing dusopropylethylamine (3 mmol). The progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the dimeric compound 141. B. Using the above procedure, but employing in place of 102, different analogs thereof, obtained according to the procedure of Preparation 8F, different compounds of formula 54 are obtained. The chemistry is shown below: -157- -158- Example 15: dimer type D-H. Reaction between (R) α-(2-methoxy-3- hydroxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, (Synthon H, 101 and 3-[4-[l-(6-bromohexyl)piperidinyl]]-6-fluorobenz[d]isoxazole, 74 to afford the ether-linked dimer 141. A. The phenol 101 (1 mmol) and the bromo compound 74 are dissolved in DMF (15 mL) and K 2 CO 3 (300 mg) and KI (50 mg) are added. The mixture is heated at 60° and the progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the compound 141. B. Using the above procedure, but employing in place 74, analogs thereof, obtained according to the procedure of Preparation 4D, different compounds of formula 40 are obtained. The chemistry is shown below: -159- -160- Example 16: dimer type C-I. Reaction between (R) α-(2,3-dimethoxyphenyl)- 4-piperidinemethanol, (Synthon G), 92, and (R) α-(2,3-dimethoxyphenyl) l-[2- (4-carboxyphenyl)ethyl]-4-piperidinemethanol, (Synthon 1, 106), to afford the dimeric amide 142. The amine 92 (1 mmol), the carboxylic acid 106 (1 mmol) and dicyclohexylcarbodumide (1 mmol) are dissolved in DMF (10 mL). The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the compound 142. The chemistry is shown below: -161- -162- Example 17: dimer type F-F. Reaction of 6-hydroxybenzo[d]isoxazole (Synthon F, 84) and l,4-di(2-bromoethyl)piperazine, 143, to afford the ether- linked dimer 144. A. The phenol 84 (2 mmol) is dissolved in DMF (10 mL) and the dibromide 143 prepared as described in Aust. J. Chem., 1997, 50, 1091, (1 mmol) K 2 CO 3 (500 mg) and KI (25 mg) are added. The mixture is heated at 60° and the progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the dimeric ether 144. B. Using the above procedure, but employing different dibromides in place of 143, different compounds of formula 47 are obtained. The chemistry is shown below: -163- -164- Example 18: dimer type G-I. Reaction between (R) l-(3-carboxypropyl)-α- (2,3-dimethoxyphenyl)-4-piperidinemethanol, 93 and (R) α-(2,3- dimethoxyphenyl) l-[2-[4-(2-aminoethylaminocarbonyl)phenyl]ethyI]-4- piperidinemethanol, 122, to afford the amide-linked dimer 145. A. The amine 122 (1 mmol), the carboxylic acid 93 (1 mmol) and dicyclohexylcarbodumide (1 mmol) are dissolved in DMF (10 mL). The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the compound 145. B. Using the above procedure, but employing in place of 122 and 93, analogs thereof, obtained as described in Preparations 14B and 7B, different compounds of formula 53 are obtained. The chemistry is shown below: -165- -166- Example 19: Reaction between (R) α-(2,3-dimethoxyphenyl)-4- piperidinemethanol, (Synthon G), 92 and (R) 4-bromo-l-(2,3- dimethoxyphenyl)butanol, 112 to afford the amine linked dimer 146. A. The amine 92 (1 mmol) and the bromo compound 112 (1 mmol) and dusopropylethylamine (2 mmol) are heated at reflux in EtOH (20 mL) The progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the dimeric compc.nd 146. B. Using the above procedure, but employing in place of 92 and 112. analogues thereof the preparations of which are described respectively in Preparations IF and 10E, different analogs of structure 146 are obtained. The chemistry is shown below: -167- Synthon G 92 -168- Example 20: Reaction between (R) 4-bromo-l-(2,3-dimethoxyphenyl)butanol, 112 and (R) 5-methylamino-l-(2,3-dimethoxyphenyl)pentanol 115 to afford the amine-linked dimer 147. The amine 115 (1 mmol) and the bromo compound 112 (1 mmol) and dusopropylethylamine (2 mmol) are heated at reflux in EtOH (20 mL) The progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the dimeric compound 147. The chemistry is shown below: -169- -170- Example 21: Reaction between (R) α-(2,3-dimethoxyphenyl)-4- piperidinemethanol, (Synthon G), 92, and l-bromo-6-(2,3- dimethoxyphenoxy)hexane, 118, to afford the amine-linked dimer 148. The amine 92 (1 mmol) and the bromo compound 118 (1 mmυl) and dusopropylethylamine (2 mmol) are heated at reflux in EtOH (20 mL) The progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the dimeric comp' " nnd 148. The chemistry is shown below: -171- ∞ -172- Example 22: Reaction between (R) α-(2,3-dimethoxyphenyl) l-[2-[4-(2- aminoethylaminocarbonyl)phenyl]ethyl]-4-piperidinemethanoI, 122 and 3-(2- chlorethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pryido[l,2-a]pyrimidin-4-one 149 to afford the amine-linked dimer 150. A. The amine 122 (1 mmol) and the chloro compound 149, prepared as described in US Patent 4,957,916 (1 mmol) were heated at reflux in MeCN (10 mL) containing KI (25 mg). The progress of the reaction is monitored by tic. When it is complete, the cooled solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the compound 150. B. Using the above procedure, but employing in place of 122, analogs of 122 as described in Preparation 14B, analogs of the compound 150 are obtained. The chemistry is shown below: -173- -174- Example 23: Reaction between (R) 4-bromo-l-(2,3-dimethoxyphenyl)butanol, 112, and (R) l-(2,3-dimethxoyphenyl)-4-mercaptobutanol, 113, to afford the thioether-linked dimer 151. A. The bromo compound 112 (1 mmol), the thiol 113 (1 mmol) and dusopropylethylamine (2 mmol) are dissolved in EtOH (10 mL). The progress of the reaction is monitored by tic. When it is complete, the solution is added to water and extracted with CH 2 C1 2 . The extract is dried and evaporated, and the residue is chromatographed to afford the thioether compound 151. B. Using the above procedure, but employing in place of 112 and 113, analogs thereof, prepared as described in Preparation IOC, the corresponding dimers analogous to 151 are obtained. The chemistry is shown below: -175- -176- While the above examples are described with respect to particular 5HT 2 receptor antagonists, the chemistry is applicable to all of the ligands described herein.

Claims: -177- HAT 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 or antagonist of the 5HT 2 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 or antagonist of the 5HT 2 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 p. 4. The multibinding compound of Claim 3 wherein each ligand is independently selected from a compound of formula IA, IB or IC: -178- -179- and analogs thereof, wherein A is H, alkyl or a direct link to the linker; and M, .10 are, independently, H or a direct link to the linker, wherein only one of A or M, .I0 is a link to the linker. 5. The multibinding compound of Claim 4 wherein the compounds are homodimers including two ligands of formula IA. 6. The multibinding compound of Claim 4 wherein the homodimers including two ligands of formula IB. 7. The multibinding compound of Claim 4 wherein the homodimers including two ligands of formula IC. 8. The multibinding compound of claim 1 wherein the ligands are selected from the group consisting of -180- and ■181- wherein A is H, alkyl, substituted alkyl, or a direct link to the linker, B is A, halo, OA or COOA 9. 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 -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) 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. -182- 10. 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 5HT, receptors and X' is a linker; and pharmaceutically-acceptable salts thereof. 11. The multibinding compound of Claim 10 wherein each ligand is independently selected from the group consisting of compounds of formula 1 A- 1 C and analogs thereof. 12. The multibinding compound of Claim 1 1 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)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'-, -NR'-C(=NR')-, -NR'-C(O)-O-, -N=C(X a )-NR'-, -P(O)(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. 13. A multibinding compound of claim 9 wherein the ligand is selected from the group consisting of: -183- -184- wherein A is H, alkyl, substituted alkyl, or a direct link to the linker, B is A, halo, OA or COOA 14. The multibinding compound of Claim 13 wherein X" has the formula: -X a -Z-(Y a -Z) m -Y b -Z-X a - wherein w 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) 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. -185- 15. A multibinding compound of claim 10 wherein the ligand is an agonist, partial agonist, or inverse agonist of the 5HT 2 receptors. 16. A multibinding compound of claim 10 wherein the ligand is an antagonist of the 5HT, receptors. 17. 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 5HT 2 receptors; and pharmaceutically-acceptable salts thereof. 18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of formula I: ( ) p (X) q I wherein each L is independently a ligand comprising an agonist, partial agonist, inverse agonist or antagonist of the 5HT, 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. 19. The pharmaceutical composition of Claim 18 wherein q is less than /?. 20. The pharmaceutical composition of Claim 19 wherein each ligand is independently selected from a compound of formula IA, IB or IC. 21. The pharmaceutical composition of Claim 18 wherein the ligand is an antagonist of the 5HT 2 receptors. 22. The pharmaceutical composition of Claim 18 wherein the ligand is a partial agonist or inverse agonist of the 5HT 2 receptors. 23. The pharmaceutical composition of Claim 18 wherein the ligand is an agonist of the 5HT, receptors. 24. The pharmaceutical composition of claim 18, wherein the ligand is selected from the group consisting of -186- -187- wherein A is H, alkyl, substituted alkyl, or a direct link to the linker, B is A, halo, OA or COOA 25. The pharmaceutical composition of Claim 19 wherein each linker independently has the formula: -X , -Z-(Y*-Z) m -Y b -Z-X a - wherein m is an integer of from 0 to 20; X s 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" and Y b at each separate occurrence are selected from the group consisting of -C(O)NR\ -NR'C(O)-, -NR'C(O) R'-, -C(=NR')-NR\ -NR'-C(=NR , -NR'-C(O)-O-, -NKIP -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. -188- 26. A pharmaceutical composition 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 5HT 2 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 consisting of compounds of formulas lA-C. 28. The pharmaceutical composition of Claim 26 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(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. 29. The pharmaceutical composition of claim 26, wherein the ligand is selected from the group consisting of -189- -190- wherein A is H, alkyl, substituted alkyl, or a direct link to the linker, B is A, halo, OA or COOA 30. The pharmaceutical composition of Claim 29 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 s 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" and Y* 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 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. -191- 31. 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 is an agonist, partial agonist, inverse agonist, partial inverse agonist, or antagonist of the 5HT 2 receptors and 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 the library prepared in (c) above to identify multimeric ligand compounds possessing multibinding properties. 32. A method for identifying multimeric ligand compounds possessing multibinding properties which method comprises: (a) identifying a library of ligands wherein each ligand is an agonist, partial agonist, inverse agonist, partial inverse agonist, or antagonist of the 5HT-, receptors and 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 the library prepared in (c) above to identify multimeric ligand compounds possessing multibinding properties. 33. The method according to Claim 31 or 32 wherein 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). 34. The method according to Claim 33 wherein the multimeric ligand compounds comprising the multimeric ligand compound library are dimeric. 35. The method according to Claim 34 wherein the dimeric ligand compounds comprising the dimeric ligand compound library are heteromeric. -192- 36. The method according to Claim 35 wherein the heteromeric ligand compound library is prepared by sequential addition of a first and second ligand. 37. The method according to Claim 31 or 32 wherein, prior to procedure (d), each member of the multimeric ligand compound library is isolated from the library. 38. The method according to Claim 37 wherein each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS). 39. The method according to Claim 31 or 32 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. 40. The method according to Claim 39 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups. 41. The method according to Claim 40 wherein the linkers are selected to have different linker lengths ranging from about 2 to lOOA. 42. The method according to Claim 31 or 32 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands. 43. The method according to Claim 42 wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohahdes, 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. 44. The method according to Claim 31 or 32 wherein the multimeric ligand compound library comprises homomeric ligand compounds. 45. The method according to Claim 31 or 32 wherein the multimeric ligand compound library comprises heteromeric ligand compounds. 46. A library of multimeric ligand compounds which may possess multivalent properties which library is prepared by the method comprising: -193- (a) identifying a ligand or a mixture of ligands wherein each ligand is an agonist, partial agonist, inverse agonist, partial inverse agonist, or antagonist of the 5HT 2 receptors and 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. 47. A library of multimeric ligand compounds which may possess multivalent properties which library is prepared by the method comprising: (a) identifying a library of ligands wherein each ligand is an agonist, partial agonist, inverse agonist, partial inverse agonist, or antagonist of the 5HT 2 receptors and 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. 48. The library according to Claim 46 or 47 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. 49. The library according to Claim 48 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups. 50. The library according to Claim 49 wherein the linkers are selected to have different linker lengths ranging from about 2 to lOOA. 51. The library according to Claim 46 or 47 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands. 52. The library according to Claim 51 wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohahdes, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof -194- 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. 53. The library according to Claim 46 or 47 wherein the multimeric ligand compound library comprises homomeric ligand compounds. 54. The library according to Claim 46 or 47 wherein the multimeric ligand compound library comprises heteromeric ligand compounds. 55. 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 are agonists, partial agonists, inverse agonists, partial inverse agonists, or antagonists of the 5HT 2 receptors and 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; (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. 56. The method according to Claim 55 wherein steps (e) and (f) are repeated from 2-50 times. 57. The method according to Claim 55 wherein steps (e) and (f) are repeated from 5-50 times. 58. A method for treating neurological disorders comprising -195- administering to a patient in need thereof an effective amount of a compound of claim 1 to treat the disorder. 59. The method of claim 58, wherein the compound is a 5-HT 2A agonist and the neurological disorder is a sleep or eating disorder. 60. The method of claim 58, wherein the compound is a 5-HT 2A antagonist and the neurological disorder is depression, anxiety, epilepsy, psychosis, schizophrenia, Alzheimer's disease, drug addiction, sleep or eating disorders. 61. The method of claim 58, wherein the compound is a 5-HT 2C agonist and the neurological disorder is a sleep or eating disorder. 62. The method of claim 58, wherein the compound is a 5-HT 2A antagonist and the neurological disorder is anorexia, an eating disorder, epilepsy, sleep disorder, psychosis, schizophrenia, Alzheimer's disease, migraine, pain, or drug addiction. 63. The method of claim 58, wherein the compound is a-5-HT 2B agonist, and the neurological disorder is a sleep or eating disorder. 64. The method of claim 58, wherein the compound is a 5-HT 2B antagonist and the neurological disorder is migraine, pain, an eating disorder, or a sleep disorder. 65. The method of claim 58, wherein the compound is a compound according to claim 2. 66. The method of claim 58, wherein the compound is a compound according to claim 4.

Inventors: GRIFFIN JOHN H, HORGER BRIAN A, NATARAJAN MAYA, GRIFFIN, JOHN, H., HORGER, BRIAN, A., NATARAJAN, MAYA
Applicants: ADVANCED MEDICINE INC, GRIFFIN JOHN H, HORGER BRIAN A, NATARAJAN MAYA, ADVANCED MEDICINE, INC., GRIFFIN, JOHN, H., HORGER, BRIAN, A., NATARAJAN, MAYA
Application year: 1999
Main classification: A61K31
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