MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5HT4 RECEPTORS

Abstract: Disclosed are multibinding compounds which are agonists, partial agonists, inverse agonists or antagonists of the 5HT4 receptors, which are involved in gastrointestinal 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 5HT4 receptors. The multibinding compounds of this invention are useful for the prophylaxis and treatment of various gastrointestinal disorders, central nervous disorders, cardiac function disorders, urinary disorders, and the like, as well as useful anti-nociceptors for analgesic use. Gastrointestinal disorders that can be treated using the compounds of this invention include gastroesophageal reflux disease (GERD), gastroparesis, functional dyspepsia, and irritable bowel syndrome.

Description: MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5HT RECEPTORS BACKGROUND OF THE INVENTION Field of the Invention This invention relates to nov el multibinding compounds (agents) that aie agonists, partial agonists, inverse agonists and antagonists for the 5HT ^ receptors. and to pharmaceutical compositions comprising such compounds The compounds are useful medications for the prophylaxis and treatment of v aπous gastrointestinal disorders, central nervous disorders, cardiac function disorders, urinary disorders. and the like, as well as useful anti-nociceptors for analgesic use References The following publications are cited in this application as superscπpt numbers: 1 Ed.. Eglen, "5HT 4 receptors in the brain and peripher ." Springer Verlag, 1998 2 Roth et al.. Pharmacol. Ther.. 79(3).2 1 -257 ( 1998. 3 Hatlebakk and Berstad, Clin. Pharmacokinetics, 31(5). 86-406 (1996) 4 Mine et al.. J. Pharm. Exp. Ther., 283.1000-1008 ( 1997) Medhurst and Kaumann, Rr. J. Pharmacol.. 1 10 1023- 11 >30 ( 1 93 ) 6 Wardle et al, Rr. J. Pharmacol., 1 18-665-670 ( 1996) All of the above publications are herein incorporated by reference in then entirety to the same extent as if each indi idual publication w as specifically and individually indicated to be incorporated by reference in its entirety State of the Art The precise control of gastointestinal (GI) motor and secretory activ itv is critically dependent on neurotransmitters and neuromodulators contained w ithin tne enteric nervous system and the endocrine cells of the gut Enteric 5- hydroxytryptamine (5HT), which accounts for a large proportion of the bodv 5H I is a key transmitter which exerts profound effects on v aπous aspects of gastrointestinal function In the penphery, 5-HT is important tor regulating v asculai and πom asuilai smooth muscle contraction, platelet aggregation, uteππe smooth muscle grow th and gastrointestinal functioning " In the gut. 5HT elicits a plethora of responses including modulation of neurotransmitter release, direct smooth muscle contractile/relaxant effects, stimulation of enteroc te secretory mechanisms modulation of peristaltic reflex and activ ation of sensory nerv es' To mediate these v aπous functions, especially in the gut. the 5HT 4 receptor is inv ol ed The 5111 , is a typical G-protein coupled receptor (GPCR) containing se en tiansmembrane spanning domains 2 Given the potential pathophysiological role of endogenous 5HT in certain GI disorders such as gastroesophageal reflux disease (GERD), gastroparesis, functional dyspepsia, and ev en irritable bow el syndrome (IBS), it is not surprising that research in this area has escalated in the past decade Irritable bo el syndrome is a pathological condition characterized bv pain and alternating periods of constipation and diarrhea The symptoms include pain bloating, constipation, diarrhea, and postprandial distension There are cunentlv no consistently effectiv e remedies av ailable for this condition, and there is a high (approximately 60-70%) placebo effect Nevertheless, it is know n that stimulation of 5HT 4 receptors in the gut produces abdominal cramps, prokmetic, and prosecretory effects and agonists, partial agonists, inv erse agonists and antagonists at this receptor site have been proposed for use in treating this disease -_>— There are currently several proposed therapies for treating IBS Compounds which are 5HT 4 agonists are useful for treating constipation- predominant IBS, and compounds which are 5HT 4 antagonists are useful foi treating diarrhea-predominant IBS A number of 5HT 4 receptor agonists that act as prokinetic agents ate currently on the market or are being dev eloped, and fall into three main classes indoles, substituted benzamides. or benzimidazoles Examples include cisapi ide (Johnson & Johnson), the most w idely used prokinetic agent, mctoclopi amide (The Merck Index, v ol 1 1 , 6063), mosapπde ( Diamppon). recently launched in lapan and Europe, and Zelmac (Nov artis). currently in Phase III clinical trials foi the treatment of IBS. 5HT antagonists hav e also been dev eloped, and SB-207266 (SmithKline Beecham) is also currently in Phase III clinical trials for the tieatmcnt of lBS. In certain tissues. 5HT ^ receptor agonists act directly on the smooth muscle or enterocyte to cause smooth muscle relaxation or stimulation of electrolyte secretion, respectively. 5HT 4 receptor activ ation can also sensitize CGRP containing sensory neurons ' Compounds which are both 5HT 4 agonists and 5HT antagonists are useful for treating GERD (heartburn), gastroparesis, functional dyspepsia and constipation Cisapride is a partial 5HT agonist that is a gastroprokmetic for conditions such as GERD, chronic gastntis, functional dyspepsia, and gastroparesis Cisapride, at least partially, acts by stimulating 5HT ^ receptors in presvnaptic nerve endings m the myenteπc plexus of the intestine This stimulates the l elease of acetvlcholine at the neuromuscular junction, strengthening tone and conttactions of the gut wall. However, first pass metabolism reduces bioav ailabihty to 40-50" .) The half-life of cisapπde is 7-10 hours in healthy indiv iduals Further, cisapride has interactions with a number of compounds such as diazepam. cimetidine and ramtidine, and is associated vv ith torsade des pointes Mosapnde is a partial 5HT → agonist gastroprokmetic that is used foi a number of conditions, such as chronic gastritis, acid reflux, and dy spepsia Mosapride binds to 5HT receptors but displaces [ H] GR- 1 13808 binding w ith a 4 3 fold lower affinity than does cisapiide Mosapiide displays higher affinity than zacopπde or metoclopramide, but low er affinity than SDZ-205557 and LY- 297524 Mosapride at a plasma concentration of 0 1 mM lacks affinitv foi the D 5HT,, 5HT 2 , l and 2 binding sites It also has low af finity foi the 5HT and benzodiazepine sues Mosapride also undergoes extensi e fust pass metabolism m a number of species, including man Studies in dogs and monkev s lev ealed respectiv e oral bioa ailabihties of S and 14% Phaimacological studies on the primary metabolites indicated that the initial metabolite retains 5HT , activ itv albeit somewhat less potent than mosapride, but is substantially moie potent as a 5HT^ antagonist Current 5HT, agonists partial agonists, inv erse agonists and antagonists often have poor bioa ailabihty due to fust pass metabolism and they can also uυ s the blood brain barrier and hav e often undesirable C\S effects w hen thev act on the 5HT 4 receptors in the brain In some cases. C S effects of 5HT, modulators are not undesirable Serotonin (5-hydroxytryptamιne. 5-HT) is involv ed in a large number of C\S processes, including the regulation of feeding behav ior, aggression, mood, perception, pain and anxiety 5HT receptors in the central nerv ous system may play an important role in cognition SL65 012 (Synthelabo Labs) is a compound that is currently m Phase I clinical trials for Alzheimer's disease In prechnical trials, it significantly impiov ed activ itv in object recognition and linear ma/e tests It would be advantageous to prov ide agents useful as agonists, partial agonists, inverse agonists and antagonists of the 5HT 4 receptors which hav e highei bioa ailabihty and which can be modified to control then CNS effects It w ould also be adv antageous to pro ide compounds w ith increased potency , increased selectivity for the 5HT receptors, and controlled efficacy (i e , partial agonism) The present invention provides such agents SUMMARY OF THE INVENTION This invention is directed to nov el multibinding compounds (agents) that are agonists, partial agonists, inv erse agonists, and antagonists of the 5H1 , receptors The multibinding compounds ot this inv ention are useful in the treatment and prevention of disorders mediated by the 5HT 4 receptois foi example, various gastrointestinal disordeis centi al nerv ous disorders cardiac function disorders, uπnary disorders, and the like as w ell as useful anti-nociceptors for analgesic use hich increase threshold of pain Examples of gastrointestinal disorders which can be treated include gastioesophageal reflux disorder (GERD), irritable bo el syndrome, constipation, diarrhea and the like Accordingly , in one of its composition aspects this inv ention pi ov ides a multibinding compound comprising troin 2 to 1 ligands co alentlv attached to one or more linkers wherein each of said ligands independently compnses an agonist, partial agonist or antagonist or the 5HT 4 receptors, and phannaceuticalh - acceptable salts thereof In another of its composition aspects, this invention prov ides a multibinding compound of formula I ! ) π (X) α wherein each L is independently a ligand compiismg an agonist partial agonist, in erse agonist or antagonist of the receptor 5HT , 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 pharmaceuticall -acceptable salts thereof Preferably, q is less than /? in the multibinding compounds of this invention Preferably, each ligand, L, in the multibinding compound of formula I is independently selected from a compound of formula IA, IB or IC: Ar'-D-E-F where Ar' is IB IC wherein: Rl and R2 are, independently, H, alkyl. substituted alkyl, a direct link to the linker, or Rl and R2 together form a carbocyclic or heterocvclic ring: R3 is H, alkyl, substituted alkyl, alkoxy, a direct link to the linker, or R2 and R3 together form a carbocyclic or heterocyclic ring; R4 is N(R) 2 , where Rl is H. alkyl, substituted alkyl, aryl, or a direct link to the linker, R5 is H, alkoxy, O-alkenyl, O-substituted alkyl. or -OC(0)Rl or a direct link to the linker, R6 is H, alkyl, substituted alkyl, aryl or a direct link to the linker, R7 is H, alkyl, substituted alkyl, aryl or a direct link to the linker, or R4-C=N-R7 form a ring selected from the group consisting of 5 or 6- membered heteroaryl and heterocvclic rings, optionally substituted with one to six substituents or one or more direct links to linker molecules, here the substituent is preferably an alkyl sulfonamide group, Dιs-C(O)-, -S0 2 -orS, E is NR, 0, S, alkyl or substituted alkyl, F is alkyl, substituted alkyl, alkyl-heterocychc, alkyl-substituted heterocychc, heterocvclic oi a direct link to the linker, with the proviso that there is at least one direct link to a linker molecule. The following formulas show examples of synthons which can be used to prepare the ligands Synthon B Synthon A (Norcisapπde) Gaster, I , et.al J Med Chem, 1993, 36,4121 WO 99/02496 Synthon C Synthon D Kato, S., et.al. Cla rk . R . ; a i rhem Lett, 1994, 4, 2477 Chem. Pharm. Bull , 1992, 40, 652 Btoorg & Med Chem L Synthon E Synthon F Buchheit, K , et al Buchheit, K , et al J Med Chem, 1995, 38,2326 J Med Chem, 1995, 38, 2331 Synthon G Clark, R., et.al Bioorg & Med Chem. Lett , 1994, 4, 2477 Synthon H Gaster, L , et al Bioorg & Med Chem Lett , 1994, 4, 667 Gaster, L , et al J Med Chem 1995 38 4760 Cla B i o In still another of its composition aspects, this invention provides a multibinding compound of formula II: L ' - X'- L ' 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. Preferably, in the multibinding compound of formula II. each ligand. L ' . is independently selected from the group consisting of ligands of the formulae 1 Λ-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-'-Z) m -Y b -Z-X α - wherein m is an integer of from 0 to 20; X Λ at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(O)-, -C(0)0-, -C(O)NR-. -C(S). -C(S )O-. -C(S)NR- or a covalent bond where R is as defined below; Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene. alkenylene, substituted alkenylene. alkynylene. substituted alkynylene. cycloalkenylene, substituted cycloalkenylene, arylene. heteroary lene. heterocyclene, or a covalent bond; Y a and Y b at each separate occurrence are selected from the group consisting of -C(0)NR'-, -NR'C(O)-. -NR ' C(O)NR'-, -C(=NR ' )-NR ' -. -NR'-C(=NR , -NR'-C(0)-0-. -X=C(X J -NR'-. -P(0)(OR , )-0-. -S(O) π CR'R"-, -S(0) n -NR ' -, -S-S- and a covalent bond: w here n is 0. 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting ot hydrogen, alkyl. substituted alkyl, cycloalky l, substituted cycloalk l, alkeny l, substituted alkenyl, cycloalkeny l, substituted cycloalkenv l, alky m l. substituted alkynyl, aryl, heteroaryl and heterocvclic In yet another of its composition aspects, this inv ention prov ides a pharmaceutical composition comprising a phannaceutically acceptable carriei and an effective amount of a multibinding compound compπsing from 2 to 1 ligands covalently attached to one or more linkers where each of said ligands independently compπses an agonist partial agonist in erse agonist or antagonist of the 5HT receptors, and phanriaceuticallv -acceptable salts theieot This inv ention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effectiv e amount of a multibinding compound of formula I or II The multibmdmg compounds of this inv ention are effectiv e agonists, partial agonists, inverse agonists or antagonists of the 5HT 4 receptois w hich ai e involved in a number of disorders Accordingly, in one of its method aspects this invention provides a method for treating v aπous disorders mediated by the 5HT_ receptors Such disorders include various gastrointestinal diseases, central nerv ous disorders, cardiac function disorders, urinary disordeis, and the like, as w ell as useful anti-nociceptors for analgesic use which increase threshold of pain When used to treat gastrointestinal disordeis. for example, the method involves administering to a patient hav ing a gastro-mtestmal disorder a pharmaceutical composition compπsing a pharmaceutically -acceptable caπier and a therapeuttcally-effectiv e amount of a multibmdmg compound comprising horn 2 to 10 ligands covalently attached to one or more linkers wherem each of said ligands independently compπses an agonist, partial agonist, inv erse agonist oi antagonist of the 5HT 4 receptors, and pharmaceutically-acceptable salts thereof This invention is also directed to general synthetic methods for generating large libraries of diverse multimeπc compounds w hich multimeπc compounds are candidates for possessing multibinding properties w ith respect to the 5HT 4 receptor The diverse multimeπc compound libraries prov ided by this inv ention are synthesized by combining a linker or linkers vv ith a hgand or ligands to piov ide for a library of multimeπc compounds wherein the linker and ligand each hav e complementary functional groups permitting cov alent linkage The hbi arv of linkers is preferably selected to hav e div erse properties such as ale cv , hnkei length, linker geometry and rigidity, hydrophihcity or hydrophobicity amphiphihcity, acidity, basicity and polaπ/abilitv and oi polan/ation The hbiai v of ligands is preferably selected to hav e div erse attachment points on the same ligand, different functional groups at the same site of otherw ise the same ligand This inv ention is also ditected to general synthetic methods for geneiating large libraries of div erse multimeπc compounds w hich multiineπc compounds ai e candidates for possessing multibmdmg properties w ith iespect to the 5HT, receptor The diverse multimeπc compound libraries prov ided by this invention are synthesized by combining a linker or linkers ith a ligand or ligands to prov ide for a library of multimeπc compounds wherein the linker and ligand each hav e complementary functional groups permitting cov alent linkage The hbrarv of linkers is preferably selected to ha e diverse properties such as valency, hnkei length, linker geometry and rigidity, hydrophihcity or hydrophobicity, amphiphihcity, acidity, basicity and polaπzabihty and/or polarization The hbrarv of ligands is preferably selected to hav e di erse attachment points on the same ligand, different functional groups at the same site of otherw ise the same hgand This invention is also directed to libraries of div erse multimeπc compound- which multimeπc compounds are candidates for possessing multibmdmg properties with respect to the 5HT 4 receptor These libraries are prepared v la th<_ methods descπbed abo e and permit the rapid and efficient ev aluation of what molecular constraints impart multibinding properties to a ligand or a class of ligands targeting the 5HT 4 receptor Accordingly, in one of its method aspects, this inv ention is directed to a method for identifying multimeπc hgand compounds possessing multibinding properties with respect to the 5HT 4 receptor w hich method comprises (a) identifying a ligand or a mixture of ligands w hich bind to the ^H I receptor wherein each hgand contains at least one reactiv e functionahtv (b) identifying a library of lmkeis w herein each hnkei in said hbrarv comprises at least tw o functional groups ha ing complementaiv i eacti itv to at least one of the reactiv e functional groups of the ligand (c) preparing a multimeπc ligand compound hbraiy by combining at least tw o stoichiometric equiv alents of the ligand or mixture ot ligands identi fied in (a) w ith the library of linkers identified in (b) under conditions w herein the complementary functional groups react to foim a cov alent linkage betw een said linker and at least two of said ligands, and (d) assaying the multimeπc ligand compounds produced in (c) abov -. to identify multimeπc hgand compounds possessing multibmdmg pioperties In another of its method aspects, this inv ention is directed to a method for identifying multimeπc ligand compounds possessing multibmdmg properties which method compπses (a) identifying a library of ligands which bind to 5HT receptor vv heiem each ligand contains at least one reactiv e functionality, (b) identifying a linker or mixture of linkers wherem each hnkei compπses at least t o functional groups hav ing complementary reacti itv to at least one of the reactive functional groups of the ligand, (c) preparing a multimeπc ligand compound library by combining at least two stoichiometric equiv alents of the library of ligands identified in (a) w ith the linker or mixture of linkers identified in (b) under conditions where the complementary functional groups react to form a cov alent linkage between said linker and at least two of said ligands, and (d) assaying the multimeric ligand compounds produced in (c) abov e to identify multimeπc ligand compounds possessing multibmdmg properties The preparation of the multimeric ligand compound library is achie ed bv either the sequential or concurrent combination of the tw o or more stoichiometric equivalents of the ligands identified in (a) w ith the linkers identified in (b) Sequential addition is preferred when a mixture of diffeient ligands is emplov ed to ensure heteromeric or multimeric compounds are prepared Concuπent addition of the ligands occurs w hen at least a portion of the multimer comounds prepared i homomultimeπc compounds The assay protocols recited in (d) can be conducted on the multimeric ligand compound library produced in (c) abov e, or preferably, each member of the library is isolated by preparativ e liquid chromatography mass spectiometry (LCMS) In one of its composition aspects, this inv ention is directed to a librar of multimeric ligand compounds w hich may possess multiv alent properties which library is prepared by the method compπsing (a) identifying a ligand or a mixture of ligands w hich bind to the 5HT receptor wherem each ligand contains at least one reactiv e functionality, (b) identifying a library of linkers herem each linker in said hbrarv comprises at least two functional groups hav ing complementary reactiv ity to at least one of the reactiv e functional groups of the ligand, and (c) preparing a multimeπc ligand compound library by combining at least two stoichiometric equiv alents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherem the complementary functional groups react to form a covalent linkage betw een said linker and at least two of said ligands In another of its composition aspects, this inv ention is directed to a hbraiv of multimeπc ligand compounds which bind to the 5HT 4 receptor w hich mav possess multivalent properties which library is prepared by the method comprising (a) identifying a hbrarv of ligands hich bind to the 5HT ^ receptor wherem each ligand contains at least one reactiv e functionahtv , (b) identifying a linker or mixture of linkers here each hnkei comprises at least tw o functional groups hav ing complementaiv reactiv ltv to at least one of the reactiv e functional groups of the ligand and (c) prepaπng a multimeric ligand compound hbrarv bv combining at least two stoichiometric equivalents of the hbrarv of ligands identi fied m ( a) w ith the linker or mixture of linkers identi fied (b) under conditions w herem the complementary functional groups react to torn, a cov alent nkage betw een said linker and at least tw o of said ligands In a preferred embodiment the hbrarv ot linkers emplov ed in either the methods or the library aspects of this inv ention is selected trom the group comprising flexible linkers, rigid hnkei s hv drophobic linkers hv diophihc lmkei s linkers of different geometry acidic linkers basic hnkei s linkers of di f ferent polaπzabihty and or polarization and amphiphihc linkers For example in on. embodiment, each of the linkers in the linker library mav comprise linkers ot different chain length and/or hav ing different complementary reacti e groups Such linker lengths can preferably range from about 2 to 100A In another preferred embodiment the ligand or mixture of ligands is selected to hav e reactiv e 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 reactiv e functionahtv includes, by way of example, carboxv he acids, carboxv lie acid hahdes carboxvl esters amines hahdes pseudohahdes isocyanates, v myl unsaturation ketones aldehydes thiols alcohols anhv dndes boronates and precursors thereof It is understood, of course, that the reactiv functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a cov alent linkage can be fonned betw een the linker and the ligand In other embodiments, the multimeric ligand compound is homomeπc ( 1 e each of the ligands is the same, although it may be attached at different points) oi heteromeric (i e , at least one of the ligands is different horn the other ligands) In addition to the combinatorial methods described herein, this inv ention provides for an iterative process for rationally ev aluating w hat molecular constraints impart multib dmg properties to a class of multimeric compounds or ligands targeting the 5HT 4 receptor Speci fically , this method aspect is dn ected to a method for identifying multimeric ligand compounds possessing multibmdmg properties ith respect to the 5HT „ i eceptoi w hich method comprises (a) preparing a first collection or iteration of multimenc compounds which is prepared by contacting at least tw o stoichiometric equiv alents of the ligand or mixture of ligands w hich target the 5HT 4 receptor w ith a linker or mixture of linkers w herein said ligand or mixture of ligands comprises at least one reactive functionality and said hnkei or mixture of linkers compnses at least tw o functional groups hav ing complementary reactiv ity to at least one of the r eactiv e functional groups of the ligand w herem said contacting is conducted undei conditions wherem the complementary functional groups react to form a cov alent linkage between said linker and at least t o of said ligands, (b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multib dmg properties, (c) repeating the process of (a) and (b) abov e until at least one multimeπc compound is found to possess multibmdmg properties, (d) ev aluating what molecular constraints imparted multibmdmg properties to the multimeπc compound or compounds found in the first iteration recited in (a)- (c) abov e, (e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibmdmg properties to the multimeric compound or compounds found in said first itei ation, (f) evaluating what molecular constraints imparted enhanced multibindmg properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) abo e. (g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints Preferably, steps (e) and (0 are repeated at least tw o times, moie pictciablv at from 2-50 times, even more preferably from 3 to 50 times, and still moie preferably at least 5-50 times BRIEF DESCRIPTION OF THE DRAW INGS Figure 1 is a schematic illustration ot methods Λ-D foi piepaπng the compounds of the present inv ention, as illustrated in the Examples Figure 2 is a schematic illustration of methods E-F tor prepaπng the compounds of the present inv ention, as illustrated in the Examples Figure 3 is a schematic illustration of methods G-K for preparing the compounds of the present inv ention, as illustrated in the Examples Figure 4 is a schematic illustration of the synthesis of compounds ot Formulae LXVII, LXVIII, LXIX, LXX and LXXI, as illustrated in the Examples Figure 5 is a schematic illustration of the synthesis of compounds ot Formulae LXXII, LXXIII, LXXI\ , LXX\ and LXX\ I as illustrated in the Examples Figure 6 illustrates examples of multibmdmg compounds comprising 2 ligands attached in different foπns to a linker Figure 7 illustrates examples of multibmdmg compounds comprising 3 ligands attached in different forms to a linker Figure 8 illustrates examples of multibmdmg compounds comprising 4 ligands attached in different forms to a linker Figure 9 illustrates examples of multibinding compounds comprising 5- 1 ligands attached in different forms to a linker DETAILED DESCRIPTION OF THE INVENTION This invention is directed to multibinding compounds w hich are agonists partial agonists, inverse agonists or antagonists of the HT , receptois pharmaceutical compositions containing such compounds and methods foi disorders mediated by 5HT 4 receptors Examples of such disorders include ar ious gastrointestinal disorders, central nervous disorders, cardiac function disoideis uπnary disorders, and the like The compounds are also useful anti-nociceptors foi analgesic use which increase threshold of pain When discussing such compounds compositions or methods, the follow ing terms hav e the follow ing meanings unless otherw ise indicated Any undefined teπns hav e their ait lecogni/ed meanings The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably hav mg from 1 to 40 carbon atoms, more preferablv 1 to 10 carbon atoms, and ev en more preferably 1 to 6 carbon atoms This term is exemplified by groups such as methyl, ethy l, /.-propyl, /5o-propy l, l. isυ- butyl, H-hexyl, /z-decyl, tetradecyl. and the like The term "substituted alkyl" refers to an alkyl group as defined abov e having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy , substituted alkoxy , cycloalky l, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acy l, acy lammo acy loxy ammo, substituted ammo, ammoacyl, ammoacyloxy, oxyammoacy l, azido cy ano, halogen, hydroxyl, keto, thioketo, carboxy l, carboxylalky l, thioaryloxy . thioheteroaryloxy. thioheterocyclooxy . thiol, thioalkoxy , substituted thioalkoxy aryl, aryloxy, heteroaryl, heteroaryloxy, heterocychc, heterocyclooxy , hvdroxvammo, alkoxvamino, nitro, -SO-alkvl. -SO-substituted alkv l. -SO-arv l -SO-heteroaryl, -SO : -alkyl, -SO, -substituted alkyl, -SO ^ -ar l and -SO ^ -heteroary 1 The tenn "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably hav ing from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms and e en 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 , -CF CH .CFL- and -CH(CH-)CH ,-) and the like. The tenn "substituted alky lene" refers to an alky lene gioup. as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents. selected from the group consisting of alkoxy. substituted alkoxy , cy cloalky l. substituted cycloalkyl, cycloalkenyl, substituted cycloalkeny l, acy l, acy lamino. acyloxy . ammo, substituted amino, aminoacyl, am oacyloxy , oxy am oacy 1. azido. cv ano. halogen, hydroxyl, keto. thioketo. carboxy l, carboxylalk 1. thioary loxy , thioheteroaryloxy, thioheterocycloox . thiol. thioalkoxy , substituted thioalkoxv . aryl, aryloxy, heteroaryl, heteroaryloxy . heterocvclic, heterocy clooxy . hydroxyamino, alkoxyammo, mtro, -SO-alk l. -SO-substituted alky l. -SO-ary l, - SO-heteroaryl, -S0 2 -alkyl, -SO : -substιtuted alkyl, -S0 2 -aryl and -SO : -heteroary 1 Additionally, such substituted alkylene groups include those w here 2 substituents on the alkylene group are fused to form one or more cycloalky l, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocvclic or heteroary l 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-ary 1 and -substituted alkylene-aryl where alkylene, substituted alky lene and ary l are defined herein Such alkaryl groups are exemplified by benzyl, phenethyl and the like. The term "alkoxy " refers to the groups alkyl-O-. alkeny 1-0-, cy cloalky l-O- cycloalkenyl-O-, and alkynyl-O-. where alkyl. alkeny l, cycloalky l, cycloalken l. and alkynyl are as defined herein. Preferred alkoxy groups are alkyl-O- and mclude, by way of example, methoxy, ethoxy , //-propoxy . .ΛO-propoxy , /.-butoxy , tert-butoxy, iec-butoxy, /.-pcntoxy . ./-hexoxy . 1 ,2-dιmethy lbutoxy, and the like The term "substituted alkoxy " refeis to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalky 1-0-. substituted cycloalkeny 1-0-, and substituted alkynyl-O- where substituted alky l, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alky ny l are as defined herein The term "alkylalkoxy " refers to the groups -alkv lene-O-alky 1. alkylene-O-substituted alky 1. substituted alkv lene-O-alky 1 and substituted alkylene-O-substituted alkyl w herein alky l. substituted alky l. alky lene and substituted alkylene are as defined herein Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by w ay of example, methylenemethoxy (-CH 2 OCH, ethylenemethoxy (-CILCILOCH ). //-propy lene-zsopiopoxv (-CH 2 CH 2 CH 2 OCH(CH,) 2 ), methy lene-. -butoxy (-CH,-O-C(CH ) ) and the like The term "alkylthioalkoxy " refers to the group -alk lene-S-alky l, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkv lene- S-substituted alkyl wherem alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein Preferred alky lthioalkoxy groups aie alky lene-S- alkyl and include, by w ay of example, methylenethromethoxy (-CFLSCH ). ethylenethiomethoxy (-CH 2 CH 2 SCH\), ;r-propylene-/5θ-thιopropoxy (-CH,CH,CH 2 SCH(CH,) 2 ), methylene-r-thiobutoxy (-CH 2 SC(CH,),) and the like The term "alkenyl" refers to a monoradical of a branched or unbranchcd unsaturated hydrocarbon group preferably hav ing from 2 to 40 caibon atoms, moi e preferably 2 to 10 carbon atoms and ev en more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of v myl unsaturation Preferred alkenyl groups include ethenyl (-CH=CH ). /.-propeny l (-CH 2 CH=CH 2 ). /50-propeny l (-C(CH )=CH 2 ), and the like The term "substituted alkenyl" refers to an alkenyl group as defined abo e 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, acyloxv, ammo, substituted ammo, aminoacyl. armnoacyloxy, oxyaminoacy 1. a/ido. cyano halogen, hydroxyl, keto, thioketo, carboxyl, carboxv lalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxv aryl, aryloxy, heteroaryl, heteroaryloxy, heterocvclic, heterocyclooxy, hydroxyammo, alkoxyamino. tro, -SO-alkyl. -SO-substituted alkyl -SO-aivl -SO-heteroaryl, -S0 2 -alkyl. -SO ; -substιtutcd alkyl, -SO ivl and -SO -heteioaivl The term "alkenylene" refers to a diradical of a branched oi unbranched unsaturated hydrocarbon group preferably having from 2 to 40 caibon 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 unsatuiation This term is exemplified by groups such as ethenylene (-CH=CH-), the piopen lene isomei (e g . -CH 2 CH=CH- and -C(CH )=CH-) and the like The term "substituted alkenylene" lefers to an alkenylene group as defined abov e having from 1 to 5 substituents, and preferably from 1 to 3 substituents. selected from the group consisting of alkoxy, substituted alkoxy. cycloalk l, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino. acyloxy, amino, substituted ammo, aminoacyl, ammoacyloxy. oxyaminoacy 1. azido, cyano. halogen, hydroxyl, keto. thioketo, carboxyl, carboxylalky 1. thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy. substituted thioalkoxy, aryl, aryloxy, heteroaryl. heteroaryloxy, heterocvclic. heteiocycloox hydroxyammo, alkox amino. mtro, -SO-alkyl, -SO-substituted alkyl. -SO-ar l - SO-heteroaryl, -S0 2 -alkyl, -S0 2 -substituted alkyl, -SO, -aryl and -S0-heteioary 1 Additionally, such substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to foπn one or more cycloalky 1. substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl. aryl. heterocvclic oi 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 alky ny 1 groups include ethynyl (-C≡CH), propargyl (-CH 2 C= CH) and the like. The term "substituted alkynyl" refers to an alkynyl group as defined abov e having from 1 to 5 substituents, and preferably 1 to 3 substituents. selected from the group consisting of alkoxy . substituted alkoxy . cy cloalk l. substituted cycloalkyl, cycloalkenyl. substituted cycloalkenyl. acy l. acylamino. acyloxy . amino, substituted amino, aminoacyl. aminoacvloxy, oxyaminoacy 1, a/ido. cy ano. halogen, hydroxyl, keto. thioketo, carboxyl, carboxylalkyl. thioaryloxy, thioheteroaryloxy, thioheterocyclooxy. thiol. thioalkoxy. substituted thioalkoxy . aryl, aryloxy, heteroaryl, heteroaryloxy, heterocvclic. heterocyclooxy, hydroxyamino. alkoxyamino, nitro. -SO-alky l, -SO-substituted alky l. -SO-ary l. -SO-heteroaryl, -SO.-alkyl. -SO.-substituted alkyl. -SO ; -aryl and -SO 2 -heteroary 1 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 hav ing at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynylene groups include ethynylene (-C≡C-), propargylene (-CH 2 C^C-) and the like. The term "substituted alkynylene" refers to an alkynylene group as defined above having from 1 to 5 substituents. and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy. cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl. acylamino, acyloxy . amino, substituted amino. aminoacyl, aminoacvloxy, oxyaminoacyl, azido, c ano. halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl. thioaryloxy, thioheteroaryloxy, thioheterocyclooxy. thiol. thioalkoxy. substituted thioalkoxy . aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy. hydroxyammo, alkoxyamino, tro. -SO-alkyl, -SO-substituted alkyl. -SO-aryl, - SO-heteroaryl, -S0 2 -alkyl, alkyl, -S0-ary 1 and -SO : -heteroary 1 The tenn "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 heterocychc- C(O)- where alkyl, substituted alkyl. cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl. aiyl. heteroaivl and heterocyclic aie as defined herein The term "acylamino" or "aminocaibon 1" refers to the group -C(0)\RR where each R is independently hydrogen, alkyl, substituted alkyl, ar l. heteroaivl heterocyclic or where both R groups are joined to form a heterocyclic group (e . morphohno) wherein alkyl. substituted alkyl. aryl. heteioaryl and heteiocvclic aie as defined herein The term "aminoacyl" refers to the group -XRC(0)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl. heteroaryl, or heterocyclic wherem alkyl, substituted alk l. aryl. heteroaryl and heterocyclic are as defined herein The term "aminoacvloxy" or "alkoxy carbonylammo" refers to the group -NRC(0)OR where each R is independently hydrogen, alk l, 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 alky l-C(0)0-. substituted alk 1- C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, aryl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0- wherein alkyl. substituted alk l. cycloalkyl, substituted cycloalkyl. aryl. heteroar l, and heterocyclic are as defined herein The tenn "aryl" refers to an unsaturated aromatic carbocyclic group ot lioin 6 to 20 carbon atoms having a single ring (e g., phenyl) or multiple condensed (fused) rings (e g , naphthyl or anthryl) Preferred ary Is include pheny 1. naphthv 1 Unless otherwise constrained by the definition for the aryl substituent. such aryl groups can optionally be substituted with from 1 to 5 substituents. prefeiably 1 to 3 substituents, selected from the group consisting of acyloxy. hydroxy. thiol. acyl, alkyl, alkoxy, alkenyl, alk nyl, cycloalkyl. cycloalkenyl, substituted alk l. substituted alkoxy, substituted alkenyl. substituted alkynyl, substituted cycloalkyl substituted cycloalkenyl, ammo, substituted amino, aminoacyl, acylamino. alkaryl. aryl, aryloxy, azido, carboxyl. carboxylalkyl. cyano, halo, mtro, heteroaryl. heteroaryloxy, heterocyclic, heterocyclooxy, aminoacvloxy, oxy acylamino. thioalkoxy, substituted thioalkoxy, thioaryloxy. thioheteroaryloxy, -SO-alkyl. -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl. -S0 2 -alkyl. -S0 2 -substituted alkyl. - SO, -aryl, -SO ^ -heteroaryl and tπhalomethyl Preferred aryl substituents include alkyl, alkoxy, halo, cyano, tro, tπhalomethyl, and thioalkoxy The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted ar l groups as also defined abo e The term "arylene" refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified bv 1.2-pheny lene, 1,3- phenylene, 1,4-pheny lene.1,2-naphthylene and the like The term "amino" refers to the group -\FL The term "substituted amino refers to the group -\RR where each R is independently selected from the gioup consisting of hydrogen, alkyl. substituted alkyl, cycloalkyl, substituted cycloalkyl. alkenyl, substituted alkenyl eveioalkeiiv] substituted cycloalkenyl. alkynyl substituted alkynyl, aivl, heteioar l and heterocyclic provided that both R ' s are not h drogen The term "carbox alkyl" or "alkoxy carbonyl" lefcis to the groups "-C(0)0-alkyl", "-C(O)O-substιtutcd alkyl" '-C(0)0-cycloalky 1", "-C(O)O- substituted cycloalkyl", "-C(0)0-alkeny 1". '-C(O)O-substιtuted alkenyl" "-C(0)0-alkynyl" and ' -C(0)0-substιtuted alkynyl" where alkv 1 substituted alkvl cycloalkyl, substituted cycloalkyl. alkenyl. substituted alkenyl. alkyn l and substituted alkynyl alkynyl are as defined herein The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 caibon atoms ha ing a single cyclic ring or multiple condensed rings Such cycloalky 1 groups include, by ay of example, single ring structuies such as cyclopropyl. cyclobutvl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like The term "substituted cycloalkyl" refers to cycloalkyl gioups having tiom 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 ammo, aminoacyl. aminoacvloxy, oxy aminoacyl. azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl. carboxylalkyl, thioaryloxy. thioheteroaryloxy, thioheterocyclooxy, thiol. thioalkoxy. substituted thioalkoxy aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyammo, alkoxyamino, tro, -SO-alkyl, -SO-substituted alkyl, -SO-ary l, -SO-heteroaryl, -SO : -alkyl, -SO-substituted alky l, -SO, -ary l and -S0 2 -heteroary l The term "cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 20 carbon atoms hav ing 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 cycloalkeny l" refeis to cy cloalkeny 1 groups hav mg from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consistmg of alkoxy, substituted alkoxy . cvcloalkyl, substituted cy cloalky l, cycloalkenyl, substituted cycloalkeny l. acyl, acy lamino, acyloxy, ammo, substituted amino, aminoacyl, aminoacvloxy, oxyaminoacyl, azido. cyano, halogen, hydroxyl, keto. thtoketo, carboxv 1. carboxylalk 1, thioaryloxy . thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy , substituted thioalkoxv . aryl, aryloxy, heteroaryl. heteroaryloxy. heterocyclic. heterocyclooxy , hydroxyammo, alkoxyamino, mtro, -SO-alkyl, -SO-substituted alky l, -SO-ary l. -SO-heteroaryl, -S0 2 -alkyl, -SO, -substituted alkyl, -S0 2 -aryl and -SO, -heteroai l The term "halo" or "halosen" refers to fluoro, chloro. bromo and lodo 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 w ithin at least one ring (if there is more than one ring). Unless otherw ise constrained by the definition for the heteroary l substituent, such heteroaryl groups can be optionally substituted vv ith 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl. alkoxy, alkenyl. alkynyl, cy cloalkyl, cycloalkenyl, substituted alkyl. substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl. substituted cy cloalkeny l. ammo, substituted am o. aminoacyl, acylamino, alkaryl. aryl, aryloxy. azido. carbox l, carboxylalkyl, cyano, halo, mtro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxv, substituted thioalkoxy, thioaryloxy thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, S0 2 -alkyl, -S0 2 -substituted alky 1, -SO,-ary 1, -SO,-heteroary 1 and tπhalomethy 1 Preferred aryl substrtuents include alkyl, alkoxy, halo, cyano, mtro, tnhalometh l and thioalkoxy Such heteroary 1 groups can hav e a single ring (e g , py πdv 1 oi fliryl) or multiple condensed rings (e g , indolizinyl or benzothieny 1) Prefeiied heteroaryls include pyπdyl, pyrrolyl and furyl The term "heteroaryloxy" refers to the group heteioaiyl-O- The term "heteroarylene" refers to the dnadical gioup derived from heteroaryl (including substituted heteroaryl), as defined abo e, and is exemplified by the groups 2, 6-pvπd lene 2.4-pyπdιvlene, 12-quιnolιnvlene, l.S- qumolmylene, 1.4-benzofuιanvlene, 2.5-pvπdnv lene, 25-ιndolenyl 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 ithin the ring Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted vv ith 1 to 5. and preferably 1 to 3 substituents, selected from the group consisting of alkoxy substituted alkoxy, cycloalkyl, substituted cycloalkyl, cvcloalkenyl. substituted cycloalkenyl, acyl, acylamino. acyloxy, amino, substituted ammo, aminoacv 1 aminoacyloxy, oxyaminoacy 1. azido cyano, halogen, hydroxyl, keto. thioketo carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy. thioheterocyclooxy. thiol thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy heterocyclic, heterocyclooxy. hydroxyammo, alkoxvamino, mtro -SO-alkvl -SO substituted alkyl, -SO-aryl. -SO-heteroaryl. -SO, -alkyl, -SO, -substituted alkyl - S0 2 -aryl and -SO,-heteroaryl Such heterocvclic groups can have a single ring or multiple condensed rings Preferred heteiocychcs include morphol o pipeπdinvl Examples of nittogen heterocvcles and heteroar ls include, but aie not limited to, pyrrole, imidazole. pvrazole. pvridme pyrazine, pvrimidine p πdazine indohzine, isoindole. indole mda/ole, puπne, quinohzine. lsoquinohne quinohne phthalazme, naphthylpvπdine, quinoxahne qumazohne, cinnohne, pteπdine caibazole, carbohne, phenanthπdinc acndine phenanthroline lsothia/ole phenazme, isoxa/ole phenoxa/me phenothiaz e lmida/olid e lmida/ohiie pipeπdine, piperazme mdohne morpholmo pipendtnvl tctrahvdrotuian l and the like as well as \-alkoxv -nitrogen containing heterocvcles The term 'heterocvclooxv" refers to the group heterocychc-O- The term 'thioheteioevclooxv' refeis to the gioup heteiocvchc-S- The tenn "heterocyclene' ieters to the duadical gioup toπned from a heterocycle, as defined herein, and is exemplified by the groups 2.6-morpholιno 2,5-morpholmo and the like The term ' oxy acylamino or "ammocarbony loxy " refers to the group -OC(0)\RR where each R is independently hydrogen, alkyl. substituted alkv! aryl, heteroaryl, or heterocyclic w herein alkyl, substituted alkvl, aryl. heteioar l and heterocyclic are as defined herein The tenn ' spiro-attached cvcloalkyl group' refers to a cvcloalkvl gioup attached to another πng via one carbon atom common to both rings The term "thiol" refers to the group -SH The term "thioalkoxy" refers to the group -S-alkvl The term "substituted thioalkoxy" refers to the group -S-substituted alk l The term "thioaryloxy" refers to the group ai l-S- wheiein the aivl gioup is as defined above including optionallv substituted ar l groups also defined abo e The term "thioheteroaryloxy" refers to the gioup heteioaryl-S- wherem the heteroaryl group is as defined above including optionallv substituted arvl gioups as also defined above As to any of the above gioups which contain one oi moie substituents it is understood, of course, that such groups do not contain anv substitution oi substitution patterns which are steπcally impractical and oi svntheticallv non feasible In addition, the compounds of this invention include all stereochcmieal isomers arising from the substitution of these compounds, hethei the isomets aie those arising in the ligands the linkers or the multivalent constructs including ihe ligands and linkers The term "phaπnaceutically -acceptable salt" lefers to salts which retain the biological effectiveness and properties of the multibmdmg compounds of this invention and which are not biologically or otherw lse undesirable In manv cases the multibmdmg compounds of this invention are capable of foπnmg acid and oi base salts by virtue of the presence of ammo and or carboxyl groups or gioups similar thereto Pharmaceuticallv -acceptable base addition salts can be prepared trom inorganic and organic bases Salts denved trom inorganic bases, include bv wav oi example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts Salts deπv ed from organic bases include, but are not limited to. salts of primary, secondary and tertiary ammes. such as alkyl ammes, dialkyl ammes tπalkyl ammes, substituted alkyl ammes, dι( substituted alkyl) ammes, tπ(substιtuted alkyl) ammes. alkenyl amines, dialkenyl ammes. tπalkenyl amines substituted alkenyl ammes. dι(substιtuted alken l) ammes. tπ( substituted alken l) ammes, cycloalkyl ammes, dι(cycloalkyl) ammes. tπ(cycloalkyl) am es, substituted cycloalkyl ammes, disubstituted cycloalkv l amine, tπsubstituted cycloalkyl am es, cycloalkeny l am es. dι(cycloalkeny l) amines tιι(cv cloalkeny l) . mines, substituted cycloalkenyl amines disubstituted cy cloalkenv l amine, tπsubstituted cycloalkenyl amines, ary l amines, diaryl amines, tπaryl amines heteroaryl amines, diheteroaryl amines, tπheteroary l ammes, heterocyclic am es diheterocychc ammes, triheterocychc amines, mixed di- and tπ-amines w here at least two of the substituents on the amine are different and aie selected from the group consisting of alkyl, substituted alky l, alkenv l, substituted alkenv l cycloalkyl, substituted cycloalky l cycloalkenv l substituted eveioalkeiiv 1 aiv l heteroaryl, heterocyclic, and the like Also included aie ammes w here the two oi three substituents. together w ith the ammo nitrogen, tonn a heteiocv clic oi heteroaryl group Examples of suitable amines include by w ay ot example onlv lsopropylamme. tπmethy l amme diethv l amine tn(. sopiopv l ) amine tι ι(// propyl) amme, ethanolamme 2-dιmethy lamιnoethanol. tiomethamine lv sme argmme, histidine, caffeine, procame. hydrabamme, cholme, betaine, ethylenediamme, glucosamme, Valkylglucamines, theobromine. purmes piperazme, pipeπdme, morphohne \-ethy lpιpeπdme. and the like It should also be understood that other carboxylic acid deriv ativ es w ould be useful the piactice of this in ention, for example, carboxylic acid amides, including carboxamides lower alkyl carboxamides, dialky l carboxamides, and the like Pharmaceutically acceptable acid addition salts mav be prepaied horn inorganic and organic acids Salts deriv ed trom inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid anu the like Salts denved from organic acids include acetic acid propionic acid glycohc acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid maleic acid, fumaπc acid, tartaric acid, citric acid benzoic acid cinnamic acid mandehc acid, methanesulfonic acid, ethanesulfo c acid -toluene-sulfomc 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 hich when bound to one or more hydroxyl, thiol, amino or carboxy l 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. thioben/yl. benzylidine. phenacy l, t-buty l- 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 w ith the nature of the product. Preferred removable thiol blocking groups include disulfide groups, acy l groups, benzyl groups, and the like. Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC). benzyloxycarbonyl (CBZ), fluorenylmethoxycarbonvl (FMOC). allvloxycarbonvl (ALOC), and the like hich can be removed by conventional conditions compatible with the nature of the product. Preferred carboxyl protecting groups include esters such as methyl, ethy 1, propyl, t-butyl etc. which can be removed by mild conditions compatible w ith 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 w here it does not. The term "ligand" as used herein denotes a compound that is an agonist partial agonist, inverse agonist or antagonist ol the 5HT 4 teceptors The specific region or regions of the ligand that is (are) recognized bv the i eceptor is designated as the "ligand domain" A ligand may be either capable of binding to a ieceptoi bv itself, or may require the presence of one or more non-hgand components foi binding (e g , Ca 2 , Mg 2 or a w ater molecule is l equired loi the binding ot a ligand to various ligand binding sites) Examples of ligands useful in this inv ention aie described herein T hose skilled in the art w ill appieciate that portions of the ligand structui e that ai e not essential for specific molecular recognition and binding activ ltv mav be v at led substantially, replaced or substituted w ith unrelated sti uctutes ( for example w ith ancillary groups as defined below ) and. in some cases omitted entnelv w ithout affecting the binding interaction The prunarx l equn ement for a ligand is that it has a ligand domain as defined abo e It is understood that the tenn hgand is not intended to be limited to compounds know n to be useful in binding to 5HT receptors (e g , know n drugs) Those skilled in the art vv ill understand that the tenn ligand can equally apply to a molecule that is not normallv associated w ith ieceptoi binding properties In addition, it should be noted that ligands that exhibit marginal activity or lack useful activ ity as monomers can be highly activ e as multivalent compounds because of the benefits conferred by multiv alency The term "multibmdmg compound or agent" refers to a compound that is capable of multiv alency, as defined below , and w hich has 2-10 ligands cov alentlv bound to one or more linkers which may be the same oi different Multibind -. compounds prov ide a biological and or therapeutic effect gi eatei than the aggregate of unlinked ligands equiv alent thereto w hich are made av ailable foi binding That is to say that the biological and or therapeutic effect of the ligands attached to the multibmdmg compound is greater than that achiev ed by the same amount of unlinked ligands made av ailable for binding to the hgand binding sites (receptors) The phrase "increased biological or therapeutic effect" includes, foi example increased affinity, increased selectiv ity for target increased specifiutv for target, increased potency, increased efficacy, decreased toxicitv, impro ed duration of activity or action, decreased side effects, increased therapeutic index, improved bioavailabihty, improved phannacokinetics. improved activity spectium. and the like. The multibinding compounds of this inv ention w ill 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 potencv of a ligand is typically proportional to its affinity foi its ligand binding site In some cases, the potency may be non-lmearly coiielated with its affinity In comparing the potency of two drugs, e g . a multibmdmg agent and the aggiegate ot its unlinked ligand, the dose-response curve of each is dctennined under identical test conditions (e.g., in an in \ιtro or in \ι\o assay, in an appropriate animal model) The finding that the multibinding agent produces an equi alent biological or therapeutic effect at a lower concentration than the aggiegate unlinked hgand i indicative of enhanced potency The term "umvalency" as used herein iefeis to a single binding interaction between one ligand as defined herein w ith one ligand binding site as defined herein It should be noted that a compound having multiple copies ligand (ot ligands) exhibit umvalency when only one ligand is interacting with a hgand binding site. Examples of umvalent 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 oi different) and two or more corresponding receptors (hgand binding sites) on one or more l eceptois w hich may be the same or different For example, two ligands connected through a linker that bind concuiicntlv to two ligand binding sites would be considered as biv alency , three ligands thus connected would be an example of tπv alency An example of tπ alent binding, illustrating a multibmdmg compound bearing three ligands ersus a mono alent binding interaction, is show n below L niv lent Inter action Tπ alent 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 ot 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 a ilable for binding to the ligand binding site (receptor) For multiv alency 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)). The term "ligand binding site" denotes the site on the 5HT 4 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 opposive of the natural agonist. Ligands ha e measurable properties that relate to the interaction of the ligand and the receptor These include the affinity of the ligand foi the receptor which relates to the energetics of the binding, the efficacv of the ligand for the receptor, which relates to the functional downstream activ ity of the ligand, the kinetics of the ligand for the receptor, hich 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 affmitv and or efficacv of a ligand across tw receptors The term "modulatory effect" refers to the ability of the ligand to change the activ ity of an agonist or antagonist through binding to a ligand binding site It is a combination of these properties w hich pro ides the foundation foi defining the nature of the functional response It should be recognized that the ligand binding sites of the ieceptor that participate in biological multiv alent binding interactions are constrained to v ai ing degrees bv their intra- and mter-moleculai associations (e >-> . such maciomoleeulai structures may be cov alently joined to a single sti uctuie, noncov alcntlv associated in a multimeric structure, embedded in a membrane oi poly meric matnx. and so on) and therefore hav e less translational and rotational freedom than if the same structures were present as monomers in solution The term "inert organic solv ent" means a solv ent w hich is inert under the conditions of the reaction being described in conjunction there ith including, bv way of example only, benzene, toluene, acetomtπle, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethy l acetate acetone, methylethyl ketone. methanol. ethanol, propanol. isopropanol. .-butanol dioxane, pyridme. and the like Unless specified to the contrary , the solv ents used m the reactions described herein are inert solv ents The term "treatment" refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes (l) pre enting the pathologic condition from occurring in a subject which may be predisposed to the condition but has not y et been diagnosed w ith tl i- condition and, accordingly, the treatment constitutes piophy lactic treatment for the disease condition, (n) inhibiting the pathologic condition, i e . ai resting its de elopment (m) relieving the pathologic condition.1 e , causing tegiession of the pathologic condition, or (iv) relie ing the conditions mediated by the pathologic condition The tenn "pathologic condition hich is modulated bv treatment ith a ligand" covers all disease states (1 e , pathologic conditions) which aie generallv ackno ledged in the art to be usefully tieated with a ligand foi the ^HI„ receptor -* m general, and those disease states which have been found to be uscfullv tieated bv a specific multibmdmg compound of our invention Such disease states include by way of example only, the treatment ot a mammal afflicted with gastioesophageal reflux disease (GERD), gastroparesis functional dvspepsia irritable bowel syndrome and the associated constipation and diarrhea and the like The tenn "therapeutically ettective amount" refeis to that amount of multibmdmg compound hich is sufficient to effect treatment, as defined abov e when administered to a mammal in need of such treatment The therapeuticallv effective amount will \ary depending upon the subject and disease condition being treated, the weight and age of the subject the severity ot the disease condition the manner of administration and the like which can readily be determined bv one ot ordinary skill in the art The term "linker", identified where appropriate bv the symbol X X oi X refers to a group or groups that covalentlv links trom 2 to 10 ligands (as identified abov e) in a manner that prov ides for a compound capable of multiv alency other features, the linker is a hgand-oπenting entity that penmts attachment ot multiple copies of a ligand ( hich mav 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 fibei and the like But it is understood that the multibinding compounds ot this mvention can be attached to a solid support if desired Foi 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, preferablv trom 10 to 10 ' and moie preferably from 10 2 to 10 4 multimeric compounds Preferably these compounds are prepared as a multiplicity of compounds in a single solution or teaction mixtuie which permits facile synthesis thereof In one embodiment the hbiarv oi multimeπc compounds can be dπectlv assav ed for multib dmg properties In another embodiment, each member of the hbrarv ot multimeric compounds is fu st isolated and, optionally characterized This member is then assav ed foi multibmdmg properties The term "collection" refers to a set of multimeric compounds w hich aie prepared either sequentiallv or concurrentlv (e g cornbinatoriallv ) The eolleetion comprises at least 2 members prefei ablv πom 2 to 10 membeis and still moi e preferably from 10 to 10" members The term "multimeπc compound" refers to compounds compi ising lrom 2 to 10 ligands cov alently connected through at least one linker w hich compounds may or may not possess multibmdmg properties (as defined herein) The term "pseudohahde" 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. tosy l, azido and cv ano gioups The extent to vvhrch multiv alent binding is realized depends upon the efficiency with which the linker or linkers that joins the ligands presents these ligands to the array of av ailable ligand binding sites Beyond presenting these ligands for multi alent interactions w ith ligand binding sites, the linker oi hnkei spatially constrains these interactions to occur ithin dimensions defined bv the linker or linkers Thus, the structural leatuies of the linker (v alencv ueometrv oπentation, size, flexibility, chemical composition, etc ) are features of multibmdmg agents that play an important role in deteπruning their activities The linkers used in this invention are selected to allow multivalent binding of ligands to the ligand binding sites of 5HT 4 receptois. wherever such sites arc located on the receptor structure The ligands are covalently attached to the linker or hnkeis using conventional chemical techniques piovidmg for covalent linkage of the ligand to the linker or linkers Reaction chemistries resulting in such linkages aie w Jl known in the art and involve the use of complcmentarv functional gioups on the linker and ligand Preferably, the complementary functional gioups on the hnkei are selected relative to the functional groups available on the ligand for bonding oi which can be introduced onto the ligand tor bonding Again, such complementaiv functional groups are well known in the ait For example reaction between a caiboxyhc acid of either the hnkei oi the ligand and a pnmaiv oi secondaiv 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 bet een an amme group of either the linker or the ligand and a sulton l hahde of the ligand or the hnkei results in formation ot a sulfonamide bond covalently linking the ligand to the linker, and reaction between an alcohol oi phenol group of either the linker or the hgand and an alkyl or aryl hahde 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 leactive groups and the resulting bonds formed bv reaction there between Table I Representativ e Complementary Binding Chemistries First Reactiv e Group Second Reactiv e Group Linkage hydroxyl isocvanate urethane amme epoxide β-hydr oxv amine sulfonyl hahde amine sulfonamide carboxyl amine amide hydroxyl alky l arv l hahde ether aldehyde amme \aCN BH_ amme ketone amme XaC XBH, amme amine isocv anate cat bam ate The linker is attached to the ligand at a position that retains ligand domain ligand binding site interaction and specificallv w hich permits the ligand domain ol the ligand to orient itself to bind to the ligand binding site Such positions and sy nthetic protocols foi linkage are w ell know n in the ar t The ter m hnkei embi ie ^ ev erything that is not considered to be part ot the hgand The relati e orientation in w hich the ligand domains are displav ed dei iv es from the particular point or points of attachment of the ligands to the linker and on the framew ork geometry The determination of w here acceptable substitutions can be made on a ligand is typically based on prior know ledge ot structure-activ itv relationships (SAR) of the hgand and or congeners and or structural information about hgand-receptor complexes (e g X-rav cry stallography, \ΛIR, and the like) Such positions and the sy nthetic methods tor cov alent attachment are w ell know n in the art Follow ing attachment to the selected hnkei (ot attachment to a significant portion of the linker, tor example 2- 10 atoms of the hnkei ) the umvalent hnker-ligand conjugate may be tested tor retention of activ itv in the relev ant assay Suitable linkers and ligands are discussed more fullv below At present, it is preferred that the multibinding agent is a biv alent compound, e g , tw o ligands w hich aie co alently linked to hnkei X Methodology The linker, w hen cov alently attached to multiple copies of the ligands provides a biocompatible, substantially non-immunoge c multibinding compound The biological activ lty of the multibmdmg compound is highlv sensitiv e to the v alency, geometrv . composition, size flexibihtv or ngiditv etc ot the linker and, in turn, on the ov erall str uctui e ot the multib dmg compound as w ell as the presence or absence of a onic or canonic charge, the r elati v e hydrophobicity/hy drophihcity of the linker and the like on the linker Accordingly, the linker is preferablv chosen to maximize the biological activ uv ot the multibinding compound The linker may be chosen to enhance the biological activ ity of the molecule In general, the linker mav be chosen fi om anv organic molecule construct that orients tw o oi more ligands to their hgand binding sites to permit multiv alencv In this regaid the linker can be considci cd as a ti amew oi k on w hich the ligands are arranged in order to bring about the desu ed hgand- oπentmg result, and thus pioduce a multibmdmg compound For example, different orientations can be achiev ed by including the framework groups containing mono- or poly cychc groups, including aiy 1 and oi heteroaryl groups, or structures incorporating one or more carbon-carbon multiple bonds (alkenyl, alkenylene. alkynyl or alkynylene groups) Other groups can also include ohgomers and polymers which are branched- oi straight-chain species In preferred embodiments, rigidity is imparted bv the presence of cy clic groups (e g ary l, heteroary l, cy cloalky l. heterocy clic. etc ) In other preferred embodiments the nng is a six or ten member ring In still further preteπed embodiments the πng is an aromatic πng such as. for example, phenyl or naphthy l Different hydrophobic hydrophihc characteristics of the linker as w ell as the presence or absence of charged moieties can readily be controlled bv the skilled artisan For example, the hy drophobic nature ot a hnkei deriv ed horn hexamethylene diamine (H 2 N(CH,) () NTL) 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 av ailable "Jeffamines". By controlling the hydrophihcity hydrophobicity, the ability of the compounds to cross the blood/brain barrier can be controlled. This can be important w hen 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 show n below The identification of an appropπate framew ork geometry and size foi ligand domain presentation are important steps in the constniction of a multibmdmg compound with enhanced activity Svstematic spatial searching strategies can be used to aid in the identification ot preferred frameworks through an iteratrve process Numerous strategies are known to those skilled in the ait ot 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 displav orientation of the ligands The process may require the use of multiple copies of the same central coie structure or combinations of different tvpes of display coics The above-described process can be extended to tπmeis and eompounds ol higher valency Assays of each of the indiv ldual compounds ot a collection geneiated as described above will lead to a subset of compounds ith the desired enhanced activities (e g , potency, selectivitv etc ) The analysis of this subset using a technique such as Ensemble Molecular Dynamics will provide a tramewoik orientation that favors the properties desired A wide diversity of linkers is commercially available (see, e g . Available Chemical Directory ( ACD)) Manv ot the linkers that are suitable for use in this invention fall into this categorv Othei 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 ot the linker can be optimized by varying the chemical composition thereof The composition of the linker can be varied in numerous vvavs to achieve the desiied physical properties for the multibmdmg 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, etheis, lipids, catio c or anionic groups, or a combination thereof Examples are giv en below , but it should be understood that v arious changes may be made and equiv alents may be substituted vv ithout 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 oi onto the linker foi example, to change the solubility of the multibmdmg compound ( in atci fats lipids, biological fluids, etc ). hy drophobicitv hvdrophihcitv . linker flexibihtv antigemcity, stability, and the like For example, the introduction of one or moi e poly(ethylene glycol) (PEG) groups onto oi into the linker enhances the hydrophihcity and w ater solubility of the multibmdmg compound, inci eases both molecular weight and molecular size and, depending on the nature of the unPEGy lated linker, may increase the in o retention time Further PEG mav decrease antigemcity and potentially enhances the ov eiall πgiditv of the hnkei Ancillary groups which enhance the w ater solubihty'hydrophihcitv of the linker and, accordingly, the resulting multibmdmg compounds are useful in practicing this invention Thus, it is w ithin the scope of the present inv ention to use ancillary groups such as, for example, small repeating units of ethv lene glycols. alcohols, pol ols (e g , glycerin, glycerol propoxylate, sacchaπdes. including mono-, ohgosacchandes, etc ), carbox lates (e g , small repeating units of glutamic acid, acrylic acid, etc ), ammes (e g , tetraethylenepentamme), and the like) to enhance the w ater solubility and or hydrophihcity of the multibmdmg compounds of this inv ention In preferred embodiments, the ancillary groun used to improv e w ater solubility hy drophihcity w ill be a polyethei The incorporation of lipophihc ancillary groups w ithin the structure of the linker to enhance the lipophihcity and or hydrophobicity of the multibmdmg compounds descπbed herein is also w ithin the scope of this inv ention Lipophihc groups useful w ith the linkers of this inv ention include, by w ay of example onlv . aryl and heteroaryl groups which, as abov e, may be either unsubstituted or substituted with other groups, but are at least substituted w ith a group which allow s their covalent attachment to the linker Other lipophihc groups useful w ith the linkers of this inv ention include fatty acid deriv ati es hich do not form bilav ers 1 aqueous medium until higher concentrations are reached Also within the scope of this invention is the use of ancillary gioups w hich result in the multibinding compound being incorporated oi anchored into a v esicle or other membranous structure such as a hposome or a micelle The tenn "lipid refers to any fatty acid deriv ativ e that is capable of forming a bilav er or a micel le such that a hydrophobic portion of the lipid material orients tow ai d the bilav ei w hile a hydrophihc portion orients tow ard the aqueous phase Hv drophihc characteπstics deriv e from the presence of phosphato. carboxvhc, sulfato, amino sulfhydryl, mtro and other like groups w ell know n in the art Hy drophobicitv could be conferred bv the inclusion of gioups that include but are not limited to long chain saturated and unsaturated aliphatic hy drocai bon gioups ot up to 20 carbon atoms and such gioups substituted bv one or more ar 1 hctei oai v 1 cycloalkyl, and or heterocyclic group(s) Pieferred lipids ate phosphoglv cei ides and sphmgohpids, representativ e examples ot w hich include phosphatidv lcholme phosphatidylethanolamme, phosphatidy lserme. phosphatidv lmositol. phosphatidic acid, palmitoyleoyl phosphatidv lcholme ly sophosphatidy lchohne lysophosphatidyl-ethanolamme, dipalmitoy lphosphatid lchohne, dioleoylphosphatidy lchohne, distearoyl-phosphatidy lchohne or dihnoleoylphosphatidv lchohne could be used Other compounds lacking phosphorus, such as sphingohpid and glycosphmgohpid families are also ithin the group designated as lipid Additionally , the amphipathic lipids described abov e may be mixed w ith other lipids including tπgly ceπdes and sterols The flexibility of the linker can be manipulated by the inclusion of ancillar y groups which are bulky and or rigid The presence of bulky or rigid gioups can hinder free rotation about bonds in the linker or bonds betw een the hnkei and the ancillary group(s) or bonds betw een the linker and the functional groups Rigid groups can include, for example those groups w hose contormational labilit y is restrained by the presence of rings and or multiple bonds w ithin the group, for example, aryl, heteroaryl, cycloalky l, cycloalkeny l, and heterocvclic groups Othet groups which can impart rigidity include poly peptide groups such as ohgo- or polyprolme chains Rigidity may also be imparted by internal hydrogen bonding or by hydrophobic collapse Bulky groups can include, for example, large atoms ions (c g iodine sulfur, metal ions, etc ) or groups containing large atoms, polv cv chc gioups including aromatic groups, non-aromatic groups and structures incorporating one or more carbon-carbon multiple bonds ( I e . alkenes and alkynes) Bulky gioups can also include ohgomers and polymers w hich are branched- or straight-chain species Species that are branched are expected to increase the rigidity ot the structure more per unit molecular w eight gain than are straight-chain species In prefened embodiments, rigidity is imparted by the presence ot cyclic groups (e g , aryl, heteroary l, cycloalkyl. heterocyclic, etc ) In other preferred embodiments, the linker comprises one or more srx-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 gioups are either positively or negativ ely charged, the similarly charged ancillary groups vv ill force the presenter linker into a configuration affording the maximum distance between each of the like charges The energetic cost of bringing the hke-chaiged groups closer to each other vv ill 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-cov alent mechanism w ill tend to hold the linker into a conformation which allow s bonding bet een the oppositely charged groups The addition of ancillary groups w hich are charged, or alternativ ely , bear a latent charge when deprotected, follow ing addition to the hnkei . including deprotection of a carboxy l, hydroxy l, thiol or ammo group by a change in pH. oxidation, reduction or other mechanisms known to those skilled in the art w hich result in removal of the protecting group, is w ithin the scope of this inv ention In view of the abov e, it is apparent that the appropriate selection of a hnkei group providing suitable orientation, restricted unrestr icted rotation, the desu ed degree of hydrophobicity hydrophihcity. etc is w ell w ithin the skill ot the ait Eliminating or reducing antige city of the multibmdmg compounds descr ibed herein is also w ithin the scope of this inv ention In cer tain cases, the antigenicitv of a multibmdmg compound may be eliminated or ι educed by use ot groups such as, for example, poly(ethylene glycol) As explained abov e, the multibmdmg compounds descnbed l.eiein comprise 2- 10 ligands attached to a linker that links the ligands m such a mannei that they are presented to the receptor for multiv alent interactions vv ith ligand binding sites thereon/ therein The linker spatially constrains these interactions to occur w ithin dimensions defined by the linker This and other factors increases the biological activity of the multibmdmg compound as compared to the same nu bei of ligands made av ailable in monobmdmg form The compounds of this inv ention are preferably represented by the empiπcal formula (L) p (X) q vv here L, X, p and q are as defined abov e This is intended to include the sev eral w ays in w hich the ligands can be linked togethei in order to achiev e the objectiv e of multiv alency , and a more detailed explanation is described below As noted previously, the linker may be considered as a framew ork to which ligands are attached Thus, it should be recognized that the ligands can be attached at any suitable position on this framew ork, for example, at the termini of a lmeai chain or at any intermediate position The simplest and most preferred multibmdmg compound is a biv alent compound which can be represented as L-X-L, w here each L is independently a hgand which may be the same or different and each X is independently the hnkei Examples of such biv alent compounds are prov ided in Figure 6. w here each shaded circle represents a ligand. A tπv alent compound could also be represented in a linear fashion, l e , as a sequence of repeated units L-X-L-X-L, in hich L is a ligand and is the same or different at each occurrence, as can X How ev er. a ti imei can also be a radial multib dmg compound comprising three ligands attached to a central core, and thus represented as (L) X here the linker X could include, foi example, an aryl or cy cloalky l group Illustrations of tπv alent and tetiav alent compounds of this inv ention are found in Figures 7 and 8 lespectiv ely w here, again, the shaded circles represent ligands Tetrav alent compounds can be represented in a linear array , e g , L-X-L-X-I -X-L in a branched array, e g . L-X-L-X-L L (a branched construct analogous to the isomers of butane -- /r-buty 1, /su-buty 1. sei - 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 deriv ativ e as abov e w ith four (4) ligands attached to the core linker The same considerations apply to higher multibmdmg compounds of this invention containing 5-10 ligands as illustrated in Figure 9 w here, as before, the shaded circles represent ligands How ev er. for multibinding agents attached to a central linker such as aryl or cycloalkyl. there is a self-ev ident 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-rmg linker (e g , biphenyl) could accommodate a larger number of ligands Certain of the abov e described compounds may alternativ ely be l epicsented as cyclic chains of the fonn X L X X X and v ariants thereof All of the abov e v ariations are intended to be w ithin the scope of the invention defined by the formula (L) P (X) With the foregoing in mind, a preferred linker may be represented by the follow ing formula -X'-Z^V-Z -Y' -Z-X 1 - m which m is an integer of from 0 to 20, X a at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(OU, -C(0)0-, -C(O)NR-. -C(S), -C(S)0-. -C(S )\R- or a cov alent bond where R is as defined below . Z is at each separate occurrence is selected from the group consisting ot alkylene, substituted alkylene. cycloalkylene. substituted cylcoalky ene. alkenylene, substituted alkenylene, alkynylene. substituted alkynylene. cycloalkenylene, substituted cycloalkenylene. arylene. heteroarylene. heterocyclene, or a covalent bond; Y d and Y b at each separate occurrence are selected from the group - consisting of: -S-S- or a covalent bond; in which: n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl. substituted alkyl. cycloalkyl. substituted cycloalky 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 bv one or more alkvl. substituted alkvl. cvcloalkvl. substituted cvcloalkv' alkenyl, substituted alkenyl, cycloalkenyl. substituted cycloalkenyl, alkynyl substituted alkynyl, aryl, heteroaryl and heterocyclic group. In one embodiment of this inv ention. the linker (i.e.. X. X ' or X") is selected those shown in Table II: Table II Representati e Linkers Linker HN-(CH 2 ) ,-NH-C(O)-(CH,)-C(O)-\H-( CH 2 ) ,-NH- -HN-(CH. 2 -NH-C(0)-(CH,) .-C(O)-\H-(CH.) ,-XH- -HN-(CH 2 • NH-C(O)-(CH 2 ),-C(O)-NΗ-(CH.).-NH- -HN-(CH 2 -NH-C(0)-(CH,) 4 -C(0)-NH-(CH ) 2 -NH- -HN-(CH. 2 -NH-C(0)-(CH,),-C(0)-XH-(CH 2 ),-NH- -HN-(CH ; 2 -NH-C(OHCH,), C(0)-XH-(CH,) 2 -XH- -HN-(CH 2 .-NH-C(O)-(CH.)--C(O)-\Η-(CH.).-NH- -HN-(CH 2 2 -NH-C(0)-(CH 2 ),-C(0)-XH-(CH,) 2 -NH- -HN-(CH 2 ,-NH-C(O)-(CH 2 VC(O)-XH-(CH 2 ),- H- -HN-(CH. 2 -NH-C(0)-(CH 2 ) lir C(0)-NH-(CH 2 ) 2 -NH- -HN-(CH 2 2 -NH-C(0)-(CH 2 ) n -C(0)-NH-(CH 2 ),-NH- -HN-(CH. 2 -NH-C(0)-(CH 2 ) 12 -C(0)-NH-(CH 2 ),-NH- -HN-(CH. 2 -NH-C(0)-Z-C(0)-NH-(CH,),-NH- where Z is 1.2-pheny ' . -HN-(CH 2 2 -NH-C(0)-Z-C(0)-NH-(CH 2 ),-NH- where Z is 1.3-phenyl -H -(CH 2 -NH-C(O)-Z-C(O)-NH-(CH ; ) .-NH- where Z is 1,4-phenyl -HN-(CH. -NH-C(0)-Z-0-Z-C(0)-NH-(CH,),-\ " H- where Z is 1.4-pheny: -HN-(CH -NH-C(0)-(CH 2 ) 2 -CH(NH-C(0)-(CH 2 ),-CH,,)-C(0)-NH-(CH 2 ),- NH- -HN-(CH 2 -NH-C(0)-(CH,)-0-(CH 2 )-C(0)-NH-(CH,) 2 -\H- -HN-(CH 2 -NH-C(0)-Z-C(0)-NH-(CH 2 ) ,-NH- vvhere Z is 5-(»-octadecyloxy)-l,3-phenyl Linker -HN-(CH 2 ) 2 -NH-C(0)-(CH,),-CH(XH-C(0)-Z)-C(0)-XH-(CH 2 ),-XH- where Z is 4-biphenyl -HN-(CH 2 ) 2 -NH-C(0)-Z-C(0)-XH-(CH,) 2 -XH- where Z is 5-(n-butyloxy)-l,3-phenyl -HN-(CH 2 ) 2 -NH-C(0)-(CH 2 ).-tra»5-(CH=CH)-C(0)-NH-(CH ) ,-NH- -HN-(CH.).-NH-C(O)-(CH.).-CH(NH-C(OHCH.) P -CH,)-C(O)-NH-(CH . NH- -HN-(CH 2 ) 2 -NH-C(0)-(CH 2 ),-CH(XH-C(0)-Z)-C(0)-NH-(CH ; -XH- where Z is 4-(n-octyl)-pheny -HN-(CH 2 )-Z-0-(CH,) f ,-0-Z-(CH,)-XH- where Z is 1,4-phenyl -HN-(CH.).-NH-C(O)-(CH.).-NH-C(O)-(CH.) -C(O)-NH-(CH.).-C(O)-NH- (CH 2 ),-NH- -HN-(CH 2 ) 2 -NH-C(0)-(CH 2 ) ,-CH(NH-C(0)-Ph)-C(0)-XH-(CH 2 ) ,-XH- -HN-(CH.).-NH-C(O)-(CH.)-N-((CH.).,-CH,)(CH.-C(O)-NH-(CH.).-\H,)- (CH 2 )-C(0)-NH-(CH 2 ) ,-XH- -H -(CH 2 ) ,-XH-C(OHCH,)-X((CH,)-CH,)-(CH,)-C(0)-NH-(CH : ) -NH- -HN-(CH.) .-NH-C(O)-(CH ,) ,-NH-C(0)-(CH,) ,-NH-C(0)-(CH,) -C(O)-NH- (CH 2 ) .-C(θ " )-NH-(CH 2 ) ,-C(6)-NH-(CH,) 2 -NH- -HN-(CH 2 ) 2 -NH-C(0)-Z-C(0)-NH-(CH 2 ) 2 -NH- vvhere Z is 5-hydroxy- 1.3-phenyl In another embodiment of this invention, the linker (i.e.. X. X' or X") has the formula: wherein each R a is independently selected from the group consisting of a cov alent bond, alkylene, substituted alkylene and arylene; each R b is independently selected from the group consisting of hydrogen, alkyl and substituted alkyl; and n ' is an integer ranging from 1 to about 20 In view of the abov e description of the linker, it is undei stood that the tenn "linker" when used in combination w ith the term "multibmdmg compound" includes both a covalently contiguous single linker (e.g , L-X-L) and multiple covalently non-contiguous linkers (L-X-L-X-L) w ithin the multib dmg compound LLgands Any compound which is an agonist, partial agonist, inv erse agonist or antagonist of the 5HT 4 receptors and w hich can be cov alently linked to a linker can be used as a ligand to prepare the compounds described herein Such ligands ar e w ell know n to those of skill in the art Preferably, each ligand. L. in the multibinding compound of formula I is independently selected from a compound of fonnula LA. IB or IC Ar'-D-E-F where Ar' is 1B or IC wherein: Rl and R2 are. independently. H, alkyl, substituted alky l. a direct link to the linker, or Rl and R2 together form a carbocyclic or heterocyclic ring: R3 is H, alkyl, substituted alkyl, alkoxy, a direct link to the linker, or R2 and R3 together form a carbocyclic or heterocyclic ring: R4 is N(R),, w here Rl is H, alkyl. substituted alky l. ar l. or a direct link to the linker, R5 is H, alkoxy, O-alkenyl, O-substituted alkyl, or -OC( 0)R l or a direct link to the linker, R6 is H, alkyl, substituted alkyl, aryl or a direct link to the linker. R7 is H, alkyl, substituted alkyl, aryl or a direct link to the linker. or R4-C-N-R7 form a ring selected from the group consisting of 5 or 6- membered heteroaryl and heterocy clic rings, optionally substituted w ith one to si x substituents or one or more direct links to linker molecules, w here the substituent is preferably an alkyl sulfonamide group. D is -C(O)-, -SO,- or S; E is NR, O. S. alkyl or substituted alkyl; F is alkyl, substituted alkyl. alkyl-heterocyclic. alkyl-substituted heterocyclic, heterocy clic or a direct link to the linker, with the proviso that there is at least one direct link to a linker molecule: Ligands of foπnula IA. IB and IC (and the precursors thereof) are ell- known in the art and can be readily prepared using art-recognized starting materials, reagents and reaction conditions. By way of illustration, the follow mg 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: Fancelli et al., Bioorganic and Med. Chem. Lett.. ( 3 )236-266 ( 1996 ): Kalo et al., Chem. Pharm. Bull.. 40(3):652-660 ( 1992); Moπe et al., Heterocvcles. 38(5): 1033-1040 ( 1994); Clark et al., Bioorganic and Med. Chem. Lett.. 4(20)2477-2480 ( 1994); Clark et al., Bioorganic and Med. Chem. Lett.. 4(20 )2481 2484 ( 1994): Clark et al.. Bioorganic and Med. Chem. Lett.. 5( 18121 19-2122 ( 1995); Buchheit et al., J. Vied. Chem.. 38:2326-2330 ( 1995 ): Buchheit et al.. L Med. Chem.. 38:2331 -2338 ( 1995); Gaster et al., 1. Med. Chem .. 38:4760-4763 (1995); Gaster et ak, J. Med. Chem., 36:4121-4123 (1993); Sober et al...1. Med. Cheπ 40:1755-1761 (1 97k Kaufmann et al.. Bioorganic and Vied. Chem. Lett.. 2(5)419-420 (1992); Schaus et ak, i u _ __d_X__£D__-, 41 H943-1955 ( 1998); Yoshikawa et ak, Jpn. J. Pharmacol., 77:53-59 (1998); Ansanay et ak, Eur. J. Pharmacol., 298:165-174 (1996); Schuurkes et ak. Therapeutics, 234(3):775-783 (1985); Briejer et ak. J. Pharmacol. And Fxp. Therapeutics, 274(2):641 -648 (1 95); Farthing. Drugs, 56:( 1 ): 10-20 ( I 998): Wardlε et ak, Brit. J. Pharmacol..118:665-670 (1996); Mcdhurst and Kau an, Brit. J. Pharmacol., 110:1023-1030 (1993); Mine et ak. J. Pharmacol..And Fxp. Therapeutics, 283(3): 1000- 1008 (199 "7 ); Hatlebakk and Berstad. Clin. Phannacokinetics, 3U5V387-406 f 1996): and PCT WO 9902496 by Janssen Phannaceuticals. Each of these patents and publications is incorporated herein by reference in its entirety to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference in its entirety. The following formulae are examples of synthons which can be used to prepare the ligands described herein: Synthon A Synthon B (Norcisapride) Gaster, I., et.al J. Med. Chem..1993, 36, 4121 WO 99/02496 Synthon C Kato, S., et.al. Chem. Pharm. Bull., 1992, 0, 652 Synthon D Clark, R., et.al. Siccrg. ά Med. Chem. Lett. 1994 , 4, 2477 Synthon E Synthon F Synthon G Schaus, J., et.al. Synthon J J. Med. Chem., 1998, 4 L 1943 Preparation of Multibinding Compounds The multibmdmg compounds of this inv ention can be prepared from readily available starting materials using the follow ing general methods and procedures It w ill be appreciated that w hei e typical or pi efen ed process conditions (l e , reaction temperatures, times, mole ratios ot reactants solv ents pressures, etc ) are giv en, other process conditions can also be used unless otherwise stated Optimum reaction conditions may v arv w ith the par ticular reactants or solv ent used, but such conditions can be dctennined bv one ski lled in the art by routine optimization procedures Additionally , as w ill be apparent to those skilled in the art conv entional protecting groups mav be necessary to prev ent certain functional gioups trom undergoing undesired reactions The choice of a suitable piotect g group for a particular functional group as ell as suitable conditions for pr otection and deprotection are vv ell know n the art For example numerous piotectmg groups and their introduction and lemov al aie descnbed in T \\ Greene and G M W uts Piotectmg Gioups in Oigamc S\ nthesιs. Second Edition, W iley. New \ ork 1991 and references cited therein Any compound w hich is an agonist partial agonist inv erse agonist oi antagonist of the 5HT → receptors can be used as a ligand in this inv ention As discussed abov e, numerous such receptor agonists, partial agonists, inv erse agonists and antagonists are known in the art and any of these know n compounds or deriv atives thereof may be employed as ligands in this inv ention Typically a compound selected for use as a ligand ill hav e at least one functional group such as an ammo, hydroxy l, thiol or carboxy l group and the like w hich allow s the compound to be readily coupled to the linker Compounds hav ing such functionality are either know n m the art or can be prepared by routine modification of known compounds using com entional reagents and procedures The patents and publications set forth abov e piov ide numerous examples of suitably functionahzed agonists, partial agonists and antagonists of the 5HT_ receptors and intermediates thereof, which mav be used as ligands in this inv ention The ligands can be cov alently attached to the linker through anv av ailable position on the ligands, prov ided that w hen the ligands are attached to the linker at least one of the ligands retains its abihtv to bind to the 5HT, receptors C ertain sites of attachment of the linker to the ligand are preferred based on know n structure-activity relationships Preferablv , the linker is attached to a site on the ligand where structure-activ ity studies show that a w ide v anetv of substituents ar e tolerated wrthout loss of receptor activ rty For example, manv know n 5H T 4 receptor agonists, partial agonists, inv erse agonists and antagonists contain among other structural features, a phenv 1 ring substituted tvpicallv in the 4-positιon w ith a chloro group and at the 2 position w ith an amine gioup Sti ucture-activ itv studies show that only v ery minor modifications are tolerated on the substituted phenv 1 ring Accordingly , the ligand is preferably not attached to the linker thi ough this phenyl ring but rather, through the ester or amide moieties or groups ot ligands thereto (represented as E-F in Formula 1 A) It w ill be understood bv those skilled in the art that the follow mg methods may be used to prepare other multibmdmg compounds of this inv ention Ligand precursors, for example, ligands containing a leav ing group or a nucleophilic group, can be cov alently linked to a linker precursor containing a nucleophilic group or a leav ing group, using conv entional leagents and conditions As show n in Figures 1 -3. methods A. B, C and F, amme groups on tw o hgand molecules can be reacted w ith the leaving groups on a linker to form a ligand dimer Methods D, E and G show the reaction of amme groups on a hnkei w ith ligands containing aldehy de groups to form dimune linkages w hich mav optionally be reduced to form diamine linkages Methods E and G show this a. a stepw ise reaction, w herem different ligands are attached to the linker in tw o separate reactions Method K show s the incorporation of synthon ligands onto the linker Additional examples of coupling reactions are show n in Figures 4 and 5 Other methods are w ell know n to those of skrll in the art for coupling molecules such as the ligands descπbed herein w ith the linker molecules descπbed herein. For example, two equiv alents of ligand precursor w ith a hahde, tosylate, or other leaving group, can be readily coupled to a linker precursor containing two nucleophilic groups, for example, amine groups, to form a dπnei The leav mg group employed in this reaction may be any conventional leav ing group including. by way of example, a halogen such as chloro, bromo or lodo, or a sulfonate group such as tosyl, mesyl and the like When the nucleophilic group is a phenol, any base which effectively deprotonates the phenolic hydroxyl group may be used, including, by way of illustration, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxrde, sodium ethoxide, tπethylannne, dnsopropylethylamme and the like Nucleophilic substitution reactions are typically conducted in an inert diluent, such as tetrahydrofuran, NN-dimethylformamide. Λ, V-dimethylacetanude. acetone, 2- butanone, l-methyl-2-pyrτolιdmone and the like After the reaction is complete the dimer is typically isolated using conv entional procedures, such as extraction filtration, chromatography and the like By way of further illustration, dimers w ith a hydiophihc linker can be formed using a hgand precursor containing nucleophilic groups and a a polyoxyethylene containing leav ing groups, for example, poly(oxyethylene) dibromide (where the number of oxvethylene units is typically an integer from 1 to about 20) In this reaction, two molar equivalents of the ligand precursor are reacted with one molar equivalent of the poly(oxyethylene) dibromide in the presence of excess potassium carbonate to afford a dimer This reaction is typically conducted in _V,N-dιmethylformamιde at a temperature ranging from about 25 °C to about 100 D C for about 6 to about 48 hours Alternatively, the linker connecting the ligands may be prepared in sev eial steps. Specifically, a ligand precursor can first be coupled to an "adapter", I e , a bifunctional group having a leav ing 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 temporanly masked with a protecting group ("PG") Representativ e examples of adapters include, b_ way of illustration, te/ . -buty l bromoacetate, 1 - Fmoc-2-bromoethylamme, l -tπty l-2-bromoethanethιol, 4-ιodobenzy l bromide propargyl bromide and the like After the ligand precursoi is coupled to the adapter and the protecting group is remov ed from the adapter ' s functional group (it a protecting group is present) to form an intermediate, tw o molar equiv alents ot the intermediate are then coupled w ith an mtennediate linker to foim a dimei Ligand precursors can be coupled w ith adapters w hich include both leav mg groups and protecting groups to form protected intermediates The leav mg gioup employed in this reaction may be any conv entional leav ing group including bv way of example, a halogen such as chloro, bromo or lodo, oi a sulfonate gioup such as tosyl, mesyl and the like Similarly any conv entional protecting gioup may be employed including, by w ay of example esters such as the methy l, to t butyl, benzyl ("Bn") and 9-fluorenylmethyl ("Fm") esters Protected intermediates can then be deprotected using con entional procedures and reagents to afford deprotected intermediates Foi example, to t butyl esters are readily hydrolyzed ith 95° 0 tπfluoroacetic acid in dichloromethane, methy l esters can be hydrolyzed w ith lithium hy droxide in tetrahydrofurarv water, benzyl esters can be removed by hvdrogenolvsis in the presence of a catalyst, such as palladium on carbon, and 9-fluorenylmethyl esters are readily cleaved using 20° o pipeπdme in DMF If desired, other w ell-know n protecting groups and deprotectmg procedures may be employed in these reactions to form deprotected intermediates Similarly, ligand precursor hav ing an adapter w ith an amme functional group can be prepared Ligand precursors can be coupled ith adapters which include leaving groups and protected amme groups to afford protected intermediates The leaving group employed in this reaction mav be any conventional leaving group Similarly, any conventional amme protecting group may be employed including, by vv ay of example, tπty 1, tei .-butoxv carbony 1 ("Boc"), benzyloxycarbonyl ("CBZ") and 9-fluorenylmethoxy -carbony 1 ("Fmoe ) 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 tπty l group is readilv removed using hydrogen chloride in acetone, a Boc group is remov ed using 95% tπfluoroacetic acid in dichloromethane, a CBZ group can be remo ed by hydrogenolysis in the presence of a catalyst, such as palladium on carbon, and a 9- fluorenylmethoxycarbonyl group is readily cleav ed using 20° o pipeπdine in D\ll to afford the deblocked amine Other well-kno n amme piotectmg gioups and deprotectmg procedures may be employed in these reactions to form amine- containing intermediates and related compounds Ligand precursors hav ing an adapter, for example, one including a tr ee carboxylic acid group or a free amme group, can be readily coupled to intermediate linkers having complementary functional groups to fonn multibinding compounds as described herein For example, hen one component includes a carboxv he acid group, and the other includes an amine group, the coupling reaction tv picallv employs a conventional peptide coupling reagent and is conducted undei conventional coupling reaction conditions, typically in the presence of a tnalkylamme, such as ethyldnsopropylamme Suitable coupling reagents for use in this reaction include, by w ay of example, carbodumides, such as ethy l-3-(3- dιmethylammo)propylcarbodumιde (EDC). dicyclohexy lcarbodnmide (DCC ) diisopropylcarbodumide (DIC) and the like, and other w ell-known coupling reagents, such as N,N '-carbonyldιιmιdazole. 2-ethoxy-l-ethoxycarbony 1-1 ,2- dihydroquinohne (EEDQ), benzotπazol-l-yloxy-tπs(dιmethylamιno)phosphonιum hexafluorophosphate (BOP), 0-(7~azabenzotπazol-l-yl)-Λ,N.N , \ - tetramethyluromum hexafluorophosphate (HATL) and the like Optionallv w ell known coupling promoters, such Λ'-hydroxysuccimmide. l-hydroxybenzotπa/ole (HOBT), l-hydroxy-7-azabenzotπazole (HOAT), Λ'N-dimethylaminopyπdine (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 dnnei 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. functionahzed intermediates. The Mitsunobu reaction is typically conducted by reacting hydroxymethyl pyrrole and the appropriate phenol using diethy l azodicarboxylate (DEAD) and triphenylphosphine at ambient temperature for about 48 hours. Deprotection, if necessary, using conventional procedures and reagents then affords the functionahzed intermediates. The functionahzed 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 diisopropylethylamme in Λ .Λ ' -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 themselv es to combinatorial approaches for identifying multimeπc compounds hich possess multibinding properties Specifically, factors such as the proper juxtaposition ot the indiv idual ligands of a multibmdmg compound w ith respect to the lelev ant arrav of binding sites on a target or targets is important in optimizing the interaction ot the multibmdmg compound with its target(s) and to maximize the biological ad antage through multivalency One approach is to identify a library ot candidate multibmdmg compounds ith properties spanning the multib dmg parameter s that are relevant for a particular target These parameters include ( 1 ) the identity of hgand(s), (2) the orientation of ligands, (3) the v alency of the construct (4) linker length, (5) linker geometry , (6) linker phy sical piopeities and (7) hnkei chemical functional groups Libraries of multimeric compounds potentially possessing multibinding properties (i e . candidate multibmdmg compounds) and comprising a multiplicity of such variables are prepared and these libraries aie then ev aluated via conventional assays corresponding to the ligand selected and the multibmdmg parameters desired Considerations relev ant to each of these v riables are set forth below Selection of Ligand. si A single ligand or set of ligands is (are) selected for incorporation into the libraπes of candidate multibmdmg compounds w hich library is directed against a particular biological target or targets. 1 e , binding to 5HT„ receptors The onlv requirement for the ligands chosen is that they are capable of interacting vv ith the selected target(s) Thus, ligands may be know n drugs, modified forms of kno n drugs, substructures of known drugs or substrates of modified forms of know n drugs (which are competent to interact ith the target) or other compounds Ligands are preferably chosen based on known fav orable properties that mav be projected to be earned ov er to or amplified multibmdmg fonns Fav orable properties include demonstrated safety and efficacy in human patients, appropriate PK/ADME profiles, synthetic accessibility , and desirable phy sical properties such as solubility, logP, etc How ev er, it is ciucial to note that ligands w hich display an unfav orable property from among the prev IOUS list may obtain a more fav orable property through the process of multibmdmg compound toπnation, 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 hen picsented in multibinding form A hgand that is potent and efficacious but not of utility because ot a non- mechamsm-related toxic side effect may hav e increased therapeutic index (increased potency relativ e to toxicity ) as a multibmdmg compound Compounds that exhibit short in o half-liv es may hav e extended half-liv es as multibinding compounds Physical properties of ligands that limit their usefulness (e g pooi bioav ailabihty due to low solubility , hydrophobicity hydrophihcity ) may be rationally modulated in multibmdmg fonns. prov iding compounds ith phy sical properties consistent w ith the desired utility Orientation. Selection of Ligand Attachment Points and Linking Chemistry Sev eral points are chosen on each ligand at w hich to attach the ligand to the linker The selected points on the ligand linker for attachment are functionah/ed to contain complementary reactiv e functional groups This permits probing the effects of presenting the ligands to their target binding sιte(s) in multiple relativ e orientations, an important multibmdmg design parameter The only requirement for choosing attachment points is that attaching to at least one of these points does not abrogate activ ity of the ligand Such points for attachment can be identi fied bv structural information w hen av ailable For example, inspection of a co-cry stal structure of a ligand bound to its target allow s one to identify one or more sites where linker attachment w ill not preclude the hgand/target interaction Alternatively, ev aluation 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 , L S Patent No 5.891 ,643. the disclosure of w hich is mco orated herein by reference m its entirety When such structural information is not available, utilization of structure-activ ity relationships (SAR) for ligands ill suggest positions where substantial structural v ariations are and are not allow ed 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 oπentations Subsequent evaluation of this library w ill indicate what positions are suitable for attachment It is important to emphasize that positions of attachment that do abrogate the activ ity of the monomeπc ligand may also be adv antageously included in candidate multibmdmg compounds in the library prov ided that such compounds bear at least one ligand attached in a manner which does not abiogate intπnsic activity This selection deriv es trom, for example, heterobiv alent interactions within the context of a single target molecule For example, consider a ligand bound to its target, and then consider modify ing this ligand bv attaching to it a second copy of the same ligand w ith a linker w hich allow s the second ligand to interact with the same target at sites proximal to the first binding site, w hich 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 achiev ed by attaching it to the linker at a position which abrogates activity of the ligand at the first binding site Another way to considei this is that the SAR of indiv idual ligands within the context of a multibmdmg structure is often different from the SAR of those same ligands in momomeπc form The foregoing discussion focused on biv alent interactions of dimeπc compounds bearing two copies of the same ligand joined to a single linker thiough different attachment points, one of which may abrogate the binding activ ity of the monomenc ligand It should also be understood that biv alent adv antage may also be attained with heterodimeric constructs bearing t o different hgands that bind to common or different targets Once the ligand attachment points hav e 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 w ith the ov erall structuie 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 av ailable hnkei s Amide bonds, ethei s. ammes, carbamates, ureas, and sulfonanndes are but a few examples of pref ei red linkages Linker Selection In the library of linkers employed to generate the library of candidate multibmdmg compounds, the selection of linkers employ ed in this library of inkers takes into consideration the follow ing factors Valency . In most instances the hbi ai y of hnkei s is initiated w ith di alent linkers The choice of hgands and proper juxtaposition of tw o ligands relativ e to their binding sites permits such molecules to exhibit target binding affinities and specificities more than sufficient to confer biological adv antage Furthermore divalent linkers or constructs are also typically of modest size such that they retain the desirable biodistπbution properties of small molecules Linker Length. Linkers are chosen m a range of lengths to allow the spanning of a range of inter-ligand distances that encompass the distance preferable for a given div alent interaction In some instances the preferred distance can be estimated rather precisely from high-resolution structural information ot targets In other instances w here 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 w here tw o binding sites are present on the same target (or target subunit for multisubumt targets), preferred linker distances are 2-20 A, with more preferred linker distances of 3- 12 A In situations vv here tw o binding sites reside on separate target sites, preferred linker distances are 20-100 A, w ith more preferred distances of 30-70 A Linker Geometry and Rigidity , The combination of ligand attachment site linker length, linker geometry, and linker rigidity detennine the possible w avs which the ligands of candidate multibinding compounds may be display ed 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 v aried as another spanning function in a multibmdmg arrav For example, linker geometry is v aried bv attaching two ligands to the ortho. meta, and para positions of a benzene πng oi in as- or t. arts-arrangements at the 1 ,1 - v s 1 ,2- v s 1.3- v s 1 4 positions around a cyclohexane core or in as- or at a point of ethylene unsaturation Linker rigidity is v aπed by controlling the number and relativ e energies of different conformational states possible for the hnkei For example a div alent compound bearing tw o ligands joined by 1 ,8-octy l linker has mote degrees of freedom, and is therefore less rigid than a compound in which the tw o ligands are attached to the 4.4' positions of a bipheny l 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 ot the candidate multibmdmg compounds in which they are included A range of linker compositions is typically selected to prov ide a range of physical properties (hydrophobicity, hydrophihcity, amphiphihcity , polarization, acidity, and basicitv ) in the candidate multibmdmg compounds The particular choice of linker phv sieal properties is made w ithin the context of the physical properties of the ligands thev join and preferably the goal is to generate molecules w ith fav orable PR ADME properties For example, linkers can be selected to av oid those that are too hydrophilic or too hydrophobic to be readily absorbed and or distπbuted in \ n o Linker Chemical Functional Groups. Linker chemical functional groups are selected to be compatible w ith 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 Having chosen a set of // ligands (// being determined by the sum of the number of different attachment points for each ligand chosen) and /// linker s bv the process outlined abov e, a library of (//' )/» candidate di alent multibinding compounds rs prepared w hich spans the relev ant multibinding design pai ametei s for a particular target For example, an aπav generated from tw o ligands. one which has two attachment points ( Al , A2) and one w hich has thiee attachment points (B l, B2, B3) joined in all possible combinations prov ide for at least 1 ^ possible combinations of multibmdmg compounds Al-Al A1-A2 Al -B l \1 -B2 \ 1 -B3 \2- A2 A2-B 1 \2-B2 A2-B3 Bl-B l B1-B2 B 1 -B3 B2-B2 B2-B3 B3-B3 When each of these combinations is joined by 10 different linkers, a hbrarv ot 150 candidate multibinding compounds results Given the combinatorial nature of the library , common chemistries are preferably used to join the reactiv e functionahes on the hgands w ith complementary reactiv e functionalities on the linkers The library there foi e lends itself to efficient parallel synthetic methods The combinatorial library can cmplov solid phase chemistries well known in the art wherem the ligand and oi hnkei is attached to a solid support Alternatrv ely and preferably , the combinatonal hbai v is prepared in the solution phase After synthesis, candidate multibmdmg compounds are optionally purified before assaying for activ ity by , for example chromatographic methods (e g , HPLC) Analysis of the Library Vaπous methods are used to characterize the properties and activ lties of the candidate multibinding compounds in the library to determine hich compounds possess multibmdmg properties Physical constants such as solubihtv under vaπous solvent conditions and logD clogD v alues can be determined A combination of NMR spectroscopy and computational methods is used to determme low -energy conformations of the candidate multibinding compounds m fluid media The ability of the members of the library to bind to the desn ed target and other targets is determined by v aπous standard methods, w hich include radiohgand displacement assays for receptor and ion channel targets and kinetie inhibition analysis for many enzy me targets //; ιtι o efficacv . such as tor ieceptoi agonrsts and antagonists, ion channel blockers. and antimicrobial activ itv . can also be determined Pharmacological data, including oral absorption, ev erted gut penetration, other pharmacokmetic parameters and efficacy data can be determined in appropriate models In this w ay , key stiuctuie-activ ity relationships are obtained for multibmdmg design paiameters which aie then used to du ect tutui e w ork The members of the library w hich exhibit multibmdmg properties, as defined herein, can be readily determined by conv entional methods First, those members which exhibit multibmdmg properties are identified by conv entional methods as described abov e including conv entional assay s (both in MH O and in Second, ascertaining the structure of those compounds which exhibit multibmdmg properties can be accomplished v la art recognized procedures Foi example, each member of the library can be encrypted or tagged w ith appropnaf information allowing determination of the structure of relev ant members at a later time See, for example. Dow er, et al , International Patent Application Publication No WO 93/061 21 , Brenner, et al . Proc. Natl . Acad. Sci.. I , S A. 89 5 1 81 ( 1992 ). and Gallop, et al , U S Patent No 5,846,839, each of w hich are incorporated herein by reference in its entirety Alternativ ely. the structure of relev ant multivalent compounds can also be determined from soluble and untagged libai ies of candidate multiv alent compounds by methods know n in the art such as those described by Hindsgaul, et al , Canadian Patent Application No 2,240,325 w hich w as published on July 1 1 , 1998 Such methods couple frontal affinity chromatography w ith mass spectroscopv to determine both the structure and relativ e binding affinities of candidate multibinding compounds to receptors The process set forth abov e for dimeπc candidate multibmdmg compounds can, of course, be extended to tπmeπc candidate compounds and higher analogs thereof Follow-up Sy nthesis and Analy sis ot Additional Libraries Based on the information obtained through analy sis of the initial hbrai v an optional component of the process is to ascertain one or more promising multibmdmg "lead' compounds as defined bv particulai r elativ e ligand orientations, linker lengths linker geometries etc Additional libraries can then be generated around these leads to prov ide for further information l egardmg sti uctui e to actrv rty relationships These array s typically bear more focused v ariations in linker structure in an effort to further optimize target affinity and or activ itv at the target (antagonism, partial agonism. etc ), and or alter phy sical properties Bv iterativ e redesign analysis using the nov el principles of multibmdmg design along with classical medicinal chemistry , biochemistry , and pharmacology approaches one is able to prepare and identify optimal multibmdmg compounds that exhibit biological advantages towards their targets and as therapeutic agents To further elaborate upon this procedure suitable div alent linkers include by w ay of example only those deriv ed from dicaiboxv hc acids, disulfonv lhalides dialdehydes, dikεtones, dihahdes, dπsocy anates, diammes, diols, mixtures of carboxy lic acids, sulfonylhahdes, aldehy des ketones hahdes, isocyanates am es and diols In each case, the carbox lic acid, sulfonylhahde, aldehyde, ketone hahde, isocvanate. amme and diol functional group is i eacted w ith a complementary functionality on the hgand to form a cov alent linkage Such complementary functionality is well known in the art as illustrated in the following table Representative Complementary Binding Chemistries First Reactive Group Second Reactive Group Linkage hydroxyl isocvanate methane amme epoxide β-hvdroxv amine sulfonyl hahde amine sulfonamide carboxyl acid amme amide hydroxyl alkyl an 1 hahde ether aldehyde amme(- reducing agent) amme ketone amιne(- reducing agent) amine amme isocvanate carbamate Exemplary linkers include the following linkers identified as VI through X-418 as set forth below Pharmaceutical Formulations When employed as pharmaceuticals, the compounds ol this inv ention are usually administered in the form of pharmaceutical compositions These compounds can be administered bv a v ariety ot routes including oral rectal, transdermal. subcutaneous, intrav enous, intramuscular, and intranasal These compounds are effective as both injectable and or al compositions Such compositions are prepared in a manner w ell know n in the pharmaceutical ar t and comprise at least one activ e compound This inv ention also includes pharmaceutical compositions w hich contain is the active ingredient one or more of the compounds described herein associated w rth pharmaceutically acceptable earners In making the compositions ot this inv ention, the active ingredient is usually mixed ith an excipient diluted bv an excipient or enclosed w ithin such a carrier w hich can be in the form ol a capsule sachet, paper or other container W hen the excipient sel v es as a diluent it can be a solid, semi-solid or liquid material w hich acts as a ehicle car r ier or medium toi the activ e ingredient Thus, the compositions can be in the torn, ot tablets pills pow ders, lozenges, sachets, cachets, elixir s suspensions emulsions solutions syrups, aerosols (as a solid or in a liquid medium), ointments containing, tor example, up to 10% bv w eight of the actrv e compound soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged pow ders In preparing a formulation, it may be necessary to null the activ e compound to provide the appropπate particle size prior to combining w ith the other ingredients If the activ e compound is substantially insoluble it ordinarily is milled to a particle size of less than 200 mesh If the activ e compound is substantially w ater soluble, the particle size is normally adjusted bv milling to prov ide a substantially uniform distribution in the iormulation, e g about 40 mesh Some examples of suitable exciprents include lactose, dextrose, sucrose sorbitol, mannitol, starches, gum acacia, calcium phosphate, algmates tragacanth gelatin, calcium silicate, microcrv stalhne cellulose polv v mv lpv rrolrdone cellulose, sterile w ater, syrup, and meth l cellulose The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil, w etting agents, emulsify ing and suspending agents preserv ing agents such as methyl- and propylhydroxy-benzoates, sw eetening agents, and flav oring agents The compositions of the inv ention can be formulated so as to prov ide quick, sustained or delayed release of the activ e ingr edient attei administr ation to the patrent by employ ing procedures know n in the art The compositions are pieferablv tormulated in a unit dosage toi each dosage containing from about 0 001 to about 1 g, moi e usually about 1 to about 3o mg, of the activ e ingredient The term "unit dosage forms" i c ei s to phv sicallv discrete units suitable as unitary dosages for human subjects and other mammals each unit contammg a predetermined quantity of activ e mater ial calculated to produce the desired therapeutic effect, in association w ith a suitable pharmaceutical excipient Preferably, the compound of formula I abov e is employ ed at no moi than about 20 w erght percent of the pharmaceutical composition moi e pr efer ablv no more than about 15 w eight percent, w ith the balance being pharmaceutically inert carrιer(s) The activ e compound is effectiv e ov er a vv ide dosage range and is genei allv administered in a pharmaceutically effectiv e amount It, w ill be understood however, that the amount of the compound actually administered w ill be determined by a physician, in the light of the relev ant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relativ e activ itv . the age vv eight, and response of the indiv idual patient, the sev enty of the pattern's sy mptoms and the like For preparing solid compositions such as tablets, the principal activ e ingredient is mixed with a pharmaceutical excrptent to form a solid preformulation composrtion containing a homogeneous mixture of a compound of the present invention When referring to these preformulation compositions as homogeneous it is meant that the actrv e ingredient is dispersed ev enly throughout the composition so that the composition may :>e readily subdiv ided into equally effectiv e unit dosage forms such as tablets, pills and capsules This solid prefonnulation is then subdiv ided into unit dosage fonns of the ty pe described abov e containing from tor example, 0 1 to about 500 mg of the activ e ingredient of the pi esent inv ention The tablets or pills of the piesent inv ention mav be coated or othei ise compounded to prov ide a dosage form affording the adv antage ot prolonged action For example, the tablet or pill can comprise an inner dosage and an outer dosag component, the latter being in the form of an en elope ov er the former Hie tw o components can be separated bv an enteric lav er hich serv es to r esist disintegration in the stomach and permit the innei component to pass intact into the duodenum or to be delayed in l elease A v aπetv of matenals can be used f or such enteric layers or coatings, such materials including a number of polv mei ic acids and mixtures of polymeric acids w ith such materials as shellac, cetv l alcohol and cellulose acetate The liquid fonns in w hich the nov el compositions ot the pi esent inv ention may be incorporated for administration orallv or bv injection include aqueous solutions, suitably flav ored sv rups. aqueous or oil suspensions, and flav ored emulsions w ith edible oils such as corn oil. cottonseed oil. sesame oil, coconut oil or peanut oil, as w ell as elixirs and similar pharmaceutical v ehicles Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solv ents, or mixtures thereof, and powders The liquid or solid compositions mav contain suitable pharmaceutically acceptable excipients as described supni Pi eterablv the compositions are administered bv the oral or nasal respiratory route toi local oi systemic effect Compositions in preferably pharmaceutically acceptable sol ents may be nebulized by use of inert gases Nebulized solutions may be inhaled directly from the nebulizing dev ice or the nebulizing dev ice mav be attached to a face mask tent, or intermittent positiv e pressure breathing machine Solution suspension, or powder compositions mav be administered, pieferably orally or nasally, from devices which deliver the fonnulation in an appropriate manner The following formulation examples illustrate representative pharmaceutical compositions of the piesent invention Formulation Example 1 Hard gelatin capsules containing the follow ing ingredients are prepared Quantity Ingredient (mg capsule) Activ e Ingredient 30 0 Starch 305 (J Magnesium stearate 5 0 The abov e ingredients are mixed and filled into hard gelatin capsules m 34ι mg quantities Formulation Example 2 A tablet formula is piepared using the ingredients below Quantity Ingredient ini -iablcu λctiv e Ingredient 25 ' ) Cellulose, microcrv stalline 200 0 Colloidal silicon dioxide 10 ( ) Steaπc acid 5 0 The components are blended and compiessed to fonn tablets each eighing 240 mg Fonnulation Example 3 A dry pow der inhaler fonnulation is prepared containing the follow ing components Ingredient _A eight _____ Activ e Ingredient 5 Lactose 95 The active ingredient is mixed w ith the lactose ctnd the mixture is added to a dry pow der inhaling appliance Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows Quantity Ingredient mi. tablet) Active Ingredient 300 mg Starch 4^ 0 mg Microcrystallme cellulose 350 mg Polyv lnylpyrro done (as 10% solution in sterile ater) 4 o mg Sodium carboxv methvl starch 4 - g Magnesium stearate o s nig Talc l.o m__ Total 1 0 e The active ingredient, starch and cellulose are passed through a \o 20 mesh U S sieve and mixed thoroughly The solution of polvv mv lpvnohdone is mixed ith the resultant powders, which aie then passed thiough a 16 mesh L S sieve The granules so produced are dried at 50 to ύ0 C and passed thiough a Hi mesh U S sieve The sodium carboxymethvl starch, magnesium stearate. and talc previously passed through a \o 30 mesh L S sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to vield tablets each weighing 120 mg Formulation Example 5 Capsules, each containing 40 mg of medicament are made as follows Quantrtv Ingredient (mg capsu j Active Ingredrent 400 mg Starch lo90mg Magnesium stearate 1.0 mg Total 1500 m.; The active ingredient, starch, and magnesium stearate are blended, passed through a No 20 mesh L S siev e. and filled into hard gelatin capsules in 150 nn 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. sie e and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary-. The mixture is then poured into a siippositorv mold of nominal 2.0 g capacity and allow ed to cool. Formulation Example ^ 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 carboxymethv l cellulose ( 1 1 %) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1 .75 g ~ Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water to 5.0 mL The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethvl cellulose in water. The sodium benzoate. flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. -8 " Fonnulation Example S \ fonnulation mav be piepared as follows Ingredient Active Ingredient Starch Magnesium stearate Total 425 o ni The active ingredient starch and magnesium steaiate aie blended passed through a No 20 mesh L S sieve, and filled into haid gelatin capsules m 4 o pi. quantities Formulauon.hxample 9 A formulation mav be prepaied as to'lows Qu_ι_ι_ι_v_ Active Ingredient ^ o mg Corn Oil 10 mL ..Example 1 A topical formulation mav be prepared as follows Ingredient Active Ingredient Emulsifying Wax Liquid Paraffin White Soft Paraffin The white soft paraffin is heated until molten The hquid paraffin and emulsifying wax ate incorporated and strned until dissolved The active mgiedie ! is added and stirring is continued until dispersed The mixture is then cooled unti' solid Another prefened formulation employed in the methods of the present invention employs transdennal delivery devices ("patches") Such transdennal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in contiolled amounts The constniction and use of transdennal patches tor the dehv eiv of pharmaceirtital agents is well know n in the art See e o- , L S Patent 5,023.252. issued June 11.1991. herein incorporated bv reference in its entirety Such patches mav be constructed tor continuous, pulsatile, or on demand delivery of phannaceutical agents Other suitable formulations foi use in the piesent in ention can be found m Remington's P ai maceuiical Sciences Mace Publishing Company Philadelphia PA Pthcd (1985) IMiJ- The multibinding compounds of this invention are agonists, partial agonists inverse agonists or antagonists ot the 5HT ^ receptois which aie known to mediate numerous disorders Accoidinglv. the multibmdmg compounds and phannaceutical compositions ot this invention aie useful the tieatmcnt and prevention of various disorders mediated bv 5HT 4 receptois Such disoideis include various gastrointestinal diseases, central nervous disoideis, cardiac function disorders, urinary disorders, and the like The compounds aie also useful anti-nociceptors for analgesic use which increase threshold ot pain Examples of gastrointestinal disorders which can be treated using the compounds descπbed herein include reflux esophagitis, gastroesophageal reflux disorder (GERD), Banett syndrome, intestinal pseudoileus, acute oi chronic gastritis, gastric or duodenal ulcer, Crohn's disease, non-ulcer dyspepsia. gastroparesis, functional dyspepsia, ulcerative colitis postgastiectomv svndrome postoperattve digestive functron failure delaved gastric emptying caused bv gasti'e neurosis, gastroptosis or diabetes, gastrointestinal disorders, and irritable bo el syndrome Other disorders include indigestion, meteoπsm. abdominal indefinite complaint, atonic constipation, chronic constipation and constipation caused b^ spinal cord injury or pelvic diaphragm failure Examples of central nerv ous disorders w hich can be treated using the compounds described herein include schizophr enia, depression, anxietv . disturbance of memory and dementia Examples of cardiac function disorders w hich can be ti eated using the compounds described herein include cardiac failure and m ocardial ischemia Examples of urinary disoidei s w hich can be treated using the compounds described herein include dysuπa caused bv ui inai v obsti uction. ui eterohth prostatomegalv , spinal coid l iurv . pelv ic diaphragm failui e and the like In addition. 5HT_ receptor antagonists show an antagonistic action on the analgesic action of cisapnde and metoclopraimde (Arzneimittel F-orschung. ol 4" pp 913-918 ( 1993)) Thus. 5HT r eceptor agonists can be useful as an anti-nocrceptor for analgesic use When used in treating or ameliorating such conditions, the compounds ot this inv ention are typically deliv ered to a patient in need of such treatment bv a pharmaceutical composition compπsing a phannaceuticallv acceptable diluent and an effecttv e amount of at least one compound of this mv ention The amount ol compound admrmstered to the patient ill v ary depending upon w hat compound and or composition is being admrmstered. the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions are admmisteted to a patient already suffering from, for example, IBS. in an amount sufficient to at least partially reduce the symptoms, t e . alternating bouts ot constipation and diarrhea Amounts effectiv e for this use ill depend on the judgment of the attending clinician depending upon factors such as the degree or sev enty of the disordei in the patient, the age, w eight and general condition of the patient, and the like Tl phaπnaceutical compositions of this invention may contain moie than one compound of the present invention As noted above, the compounds administered to a patient are in the form ot pharmaceutical compositions described above which can be admimsteied bv a variety of routes including oial, rectal, transdennal, subcutaneous, intravenous intramuscular, etc These compounds are effective as both injectable and oral deliverable pharmaceutical compositions Such compositions are prepared m a manner ell known in the phannaceutical art and compπse at least on activ e compound The multibmdmg compounds of this invention can also be admmisteicd the fonn of pro-drugs, I e , as derivatives hich are converted into a biologically active compound in \ι\o Such pro-drugs will tvpicallv include compounds which, for example, a carboxv he acid group, a hvdroxv 1 gioup or a thiol gioup is converted to a biologically liable gioup such as άi\ estei lactone oi thioestei gioup which ill hvdrol e in \ o to reinstate the lespective group The compounds can be assaved to identify which of the multimeric ligand compounds possess multib dmg properties First, one identifies a ligand oi 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 ot the ligand Next, one prepares a multimeπc ligand compound hbrarv bv combining at least two stoichiometric equivalents of the hgand or mixture ot hgands ith the library of linkers under conditions wherem the complementary functional ioun react to form a covalent linkage between the linker and at least two ot the ligands The multimeric ligand compounds produced in the library can be assaved to identify multimeric ligand compounds hich possess multibinding pioperties The method can also be perfonned using a library of hgands and a linker or nuxtun of linkers The preparation of the multimeric ligand compound library can be achie ed by either the sequential or concurrent combination of the t o or moie stoichiometric equivalents ot the ligands with the hnkeis The multimeric hgand compounds can be dimeπc for example, homomenc 01 heteromeric V heteromeric hgand compound hbrarv can be prepaied bv sequentially adding a fust and second hgand Each member of the multimeric ligand compound hbrarv can be isolated from the library, for example bv preparati e liquid chromatographv mass spectiometry (LCMS) The linker or linkers can be flexible hnkeis iigi lmk s hydrophobic linkers, hydrophilic hnkeis linkers of dilteient geometry acidic linkers, basic hnkeis, linkers of diffeient polarization and or polanzabihtv oi amphiphilic lrnkers The linkers can include linkers ot diffeient chain lengths and or which have different complementary reactive groups In one embodiment the linkers are selected to have diffeient linker lengths langmg horn about 2 to 100A The hgand oi nnxtuie ot ligands can have leacti e functionality at dilLic'u sites on the ligands The reacti e functionality can be. toi example carboxv he acrds, carboxylic acid halides. carboxv 1 esters, amines, hahdes. 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 multimeπc ligand compounds can thus be formed which possesses multivalent properties Multimeric ligand compounds possessing multib dmg properties can oe identified in an iterative method bv prepaπng a first collection or iteiation ol multimeπc compounds by contacting at least two stoichiometiic equivalents ot the ligand or mixture of ligands vv Inch target the 5HT receptors w ith a linker oi mixture of linkers, where the ligand or mixture of hgands includes at least one reactive functionality and the linker or mixture of hnkeis includes at least t o functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand The hgand(s) and lmkeι(s) are reacted undei conditions which fonn a covalent linkage between the linker and at least two ol the ligands The first collection or iteration of multimeric compounds can be assaved 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 multibmdmg properties By evaluating the particular molecular constiaints which are imparted or are consistent with imparting multibmdmg properties to the multimeπc compound or compounds in the first iteration a second collection oi iteration of multimeπc compounds which elaborates upon the particulai mo ciila constraints can be assaved and the steps optionallv lepeated to further elaboiatc upon said molecular constraints For example, the steps can be lepeated from between 2 and 50 times, more preferably, between 5 and 50 times The following synthetic and biological examples aie otlered to illiistnue this invention and are not to be constiued in anv wav as limiting the scope oi this invention Unless other ise stated all temperatures aie in degiees Celsius EXAMPLES In the examples below . the follow mg abbrev lations hav e the follow g meanings If an abbreviation is not defined, it has its generally accepted meanm-. A Angstroms cm centimeter DCC dicvclohexvl carbodnmide DMSO dimethv lsulfoxide EDTA ethv lenedianunetetraacetic acid o gram HPLC high perfonuance liquid chromatography MEM minimal essential medium mg milligram MIC minimum inhibitory concentration nun minute mL milhhtei mm millimeter mmol = millimol N = normal THF = tetrahydrofuran μL = microliters m = microns ANALYTICAL EXAMPLES Example 1 ; 5-HT Receptor Binding Test C J. Grossman et ak, British Journal of Pharmacology, vol. 1 9. pp. 1 S-624 ( 1 993 )), discloses a specific 5HT 4 receptor binding test using, as a tracer hgand. a tritiated compound ( l -(2-methvisullbnviamιnoethv l )-piperidin-4-v Imethv l ester substituted by tritium) (hereinafter to be referred to as 3H:GR 1 13S0S). Speci fical lv . crude synapse membrane samples can be prepared from guinea pig striatum. suspended in 50 mM HEPES buffer (pH 7.4) and used for testing. The compounds to be tested and 3H:GR 1 1 3S0S ( final concentration o. l nM ) can be added to this suspension and allow ed to react at 37 C. Thirty- minutes later. the reaction mixture can be filtered by suction with a cell harvester. The filter can be washed with 50 mM HEPES buffer, and the radioactivity on the filter counted by a liquid scintillation counter. The non-specific binding can be determined in the presence of 1 μM GR1 13808. The concentration of the test compound necessar y for 50% inhibition (IC,,,) and Ki value can then be detenuined. Example 2: Contraction of the Isolated Guinea Pig Ascending Colon About 3 cm of a long ascending colon segment can be taken from male Hartley Guinea pig and suspended in 10 ml of a Tyrode solution ventilated w ith a mixed gas of oxygen ( 95%) and CO : (5% ) at 3" C with a load of 2 g. The contraction can be isotonically measured via a transducer. After an equibilium period of about 30 min, the test compound can be administered non-cumulatively from lower concentrations, and concentration-dependent contraction can be measured. The test compound can be administered, for example, at 15 minutes intervals. Then, contraction by the compound in the presence of a known 5HU receptor antagonist. 4-amino-3-chloro-6-methoxybenzoic acid- 2-diethylamino-ethyl ester (0.3 μM. hereinafter to be referred to as SDZ 205-557 ) can be determined, and antagonistic effect on the reaction by SDZ 205-557 confirmed. The contraction by the test compound can be evaluated based on the ratio of reaction relative to mean contraction induced by methacholine (30 μM ) administered before and after each detenuination of concentration-dependent contraction. The contraction can be prohibit-convertcd using the maximum alue o\ concentration-response curve as 100. and expressed by EC .,, as determined from linear regression. Example 3: Promotion of Postcihal Enterokinesis of Dog W ithout Anesthesia Ito et ak. Journal of Smooth Muscle Research, vol. 13. pp. 33-43 ( 1976 ) discloses a method of promoting poscibal enterokinesis in dogs w ithout anesthesia. In this method, male and female adult mongrel dogs can be subjected to laparotom under pentobarbital anesthesia, and a force transducer sutured to the serous membrane of various sites of gastrointestinal tract in the direction of the circular muscle. After about two weeks recovery period, posteibal gastrointestinal motilitv can be measured. Example 4: Determination of Bioavailability in Rats A compound to be evaluated can be administered to female SD rats ( 3 per group) at a dosage of about 2.5 mg, kg ( i.v.) and 10 mg kg (p.o. ). Blood samples can be taken with the passage of time, and the concentration of the drug in plasma measured, for example, with high performance liquid chromatography. The bioavailabihty can then be calculated. Example 5: Absorption hy Small Intestine in Rat Male SD rats (3 per group) can be fasted overnight and subjected to laparotomv under ether anesthesia, and the upper part of small intestine ligated to form a loop ( 15-20 cm in length). The drug can be dissolved in 5% glucose to the drug concentration of 5 mg 'l O ml, and 10 ml kg thereof can be injected into the loop. At 2 hours from the drug injection, the loop can be removed, washed w ith 100 ml of 0.1 N hydrochloric acid-methanol ( 3:7), and the drug concentration determined by high perfonuance liquid chromatography . Example 6; Stimulation of Defecation in Mousf Male ddY mice can be placed in partition box. and the number and w et weight of feces excreted for 2 hours from immediately- after oral administration ol the compounds can be measured. Example 7; Promotion of Colonic Transit in Guinea Pig Male Hartley guinea pigs can be subjected to laparotomv under ether anesthesia, and a polyethylene tube inserted into the beginning of colon. The other end can be passed under the skin to be exposed from the neck and fixed there. At day 5 postoperation, Evans blue solution can be injected into the colon through the polyethylene tube. One hour later, the colon can be remo ed, and the range of the Evans blue solution measured, calculated relativ e to the entire length of the colon and expressed as a transit ratio. The compounds can be orallv administered one hour before injection of the Evans blue solution. Example 8; Promotion of Gastric Emptying in Rats Barium pellets (ca. 1 mm diameter) coated with poly styrene can be intragastrically administered to male Wistar rats. One hour later, the stomach can be removed, and the remaining pellets counted. The compound to be evaluated can be orally administered one hour before administration of the pellets. The promotion ratio can be calculated from the comparison of the number of remaining pellets and the number thereof in the group administered with vehicle. Other methods for evaluating the compounds of the present invention include the guinea pig ileum twitch, rat esophagus relaxation and dog heidenhain pouch. Such methods are well known to those of skill in the art. PREPARATIYE EXAMPLES In the examples which follow , compounds I-XXYIII are dimers of agonist ligands, compounds XXIX through XXXYIII are dimers of antagonist ligands. and compounds XXXIX through LXYI are dimers of mixed agonist antagonist ligands. Example 1 Preparation of a compound of Formula I via method A. A. A mixture of 50 mmols of Synthon A, 25 mmols of . '-dibromo-p-xv lene and 50 mmols of potassium carbonate in 20 mL of DMF is w anned as necessary and the reaction followed by TLC. When judged complete, it is partitioned between isopropyl acetate and water and the aqueous phase back extracted w ith isopropyl acetate. The combined organic extracts are w ashed 3X water, dried ovei sodium sulfate, filtered and the solvent removed in vacuo to afford material of Formula I. B. In a similar manner other analogs of Formula I mav be prepared using alternative dihalo linker molecules. Other compounds indicated as synthesized bv method A may also be prepared in this manner. Example 2 Preparation of a compound of Formula IX v ia method B Synthon B Example of Formula IX Method B A. A mixture of 50 mmols of Synthon B. 50 mmols of 1 .4-dιbromobutane and 50 mmols of potassium carbonate in 20 mL of DMF is wanned as necessary and the reaction followed by TLC. When judged complete, it is partitioned betw een isopropyl acetate and water and the aqueous phase back extracted with isopropv 1 acetate. The combined organic extracts are washed 3X water, dried over sodium sulfate, filtered and the solvent removed in vacuo to afford a mono-alky lated intermediate which is purified by crystallization or chromatography. A mixture of 20 mmols of the above intermediate, 20 mmols of Synthon C and 20 mmols of potassium carbonate in 20 mL of DMF is warmed as necessar y and the reaction followed by TLC. When judged complete, it is partitioned between isopropyl acetate and water and the aqueous phase back extracted w ith isopropyl acetate. The combined organic extracts are w ashed 3X ith w ater, dried over sodium sulfate. filtered and the sol ent removed ;/; vat no to afford material o i Formula IX. B. In a similar manner other analogs of Formula IX mav- be prepared using alternative dihalo linker molecules. Other compounds indicated as synthesized bv method B may also be prepared in this manner. E _ir_ιpl_Li Preparation of a compound of Formula XYII v ia method G. A. A mixture of 50 mmols of Synthon C. 50 mmols of 1 ,4-dιbromobutane and 50 mmols of potassium carbonate in 20 mL of DMF is w anned as necessary and the reaction followed by TLC. When judged complete, it is partitioned betw een isopropyl acetate and water and the aqueous phase back extracted w ith isopropv 1 acetate. The combined organic extracts are w ashed 3X ith w ater, dried over sodium sulfate, filtered and the solvent remov ed //; vacuo to afford mono-alkv lated product which is purified by crystallization or chromatography . This material ( 2u mmols) is dissolv ed in methanol and 2') mmols of sodium azide and a small amount of water added. The reaction is heated to reflux and w hen complete, the mixture is filtered of any precipitate and hy drogenated at atmospheric pressure in the usual manner with Pd C. The resultant product is purified by chromatography or crystallization to afford intermediate 1. A mixture of 25 mmols of thiose icarbazide l oo mL of ethanol is treated with 30 mmols of iodomethane and 30 mmols of potassium carbonate. After 1 h . 25 mmols of intermediate 1 is added and the mixture heated to reflux. When complete, the reaction is concentrated and the residue partitioned bet een ethv 1 acetate and water. The aqueous phase is back extracted w ith ethv 1 acetate and the combined organic extracts are washed 3X w ith water, dried ov er sodium sulfate. filtered and the solvent removed in vacuo to afford aminoguanidine intermediate 2 which is purified by crystallization or chromatography. A solution of 10 mmols of intennediate 2 and 20 mmols of Sy nthon E 5o mL of methanol is acidified to pH 3-4 with cone. HCI and the reaction is refiuxed for two hours. The reaction mixture is concentrated and the residue converted to it- hydrochloride salt with methanol and ethereal HCI. This material is purified bv crystallization to afford a sample of Formula XVTI. B. In a similar manner other analogs of Formula XYII may- be prepared using alternative dihalo linker molecules. Other compounds indicated as synthesized by method G may also be prepared in this manner. Preparation of a compound of Formula XXII via method C. Intermediate 3 A. A solution of 50 mmols of the trifluoroacetamide of Synthon G in 100 mL of THF is cooled to -30C and 50 mL of 1 X LDA in THF added. After 30 min. 50 mmols of 1 ,4-dibromobutane is added and the reaction warmed to room temp, and heated further if necessary. When judged complete, it is concentrated and partitioned between isopropyl acetate and water and the aqueous phase back extracted with isopropyl acetate. The combined organic extracts are washed 3X with water, dried over sodium sulfate, filtered and the solvent removed in vacuo to afford material of intermediate 3. A mixture of 30 mmols of intermediate 3, 30 mmols of Synthon D and 30 mmols of potassium carbonate in 20 mL of DMF is wanned as necessary and the reaction followed by TLC. When j udged complete, it is partitioned between isopropyl acetate and water and the aqueous phase back extracted w ith isopropyl acetate. The combined organic extracts are washed 3X with water, dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue is dissol ed in 30 mL of methanol and 30 mL of 1 ____ NaOH added. When hydrolysis is complete, the reaction is concentrated in vacuo and the residue worked up w ith ethyl acetate and water. The crude product is puri fied bv chromatography or cr y stallization to afford material of Formula XXII. B. In a similar manner other analogs of Fonnula XXII may- be prepared using alternative dihalo linker molecules. Other compounds indicated as synthesized bv method C may also be prepared in this manner. Preparation of a compound of Formula XXIII via method D. Intermediate 4 Synthon E 2 equiv. Example of Formula XXIII Method D A. A mixture of 25 mmols of thiosemicarbazide in 1 0 mL of ethanol is treated with 30 mmols of iodomethane and 30 mmols of potassium carbonate. After 1 hr.. 12 mmols of 1.3-dιammopropane is added and the mixture heated to refiux Vv hen complete, the reaction is cooled and the solution of mtenuediate 4 is used w ithout further puπfrcation A solution of 25 mmols of Sv nthon E in ethanol is added and the mixture acidified to pH 3-4 w ith cone HCI and the reaction refluxed for tw o hours. The reaction is concentrated and the residue conv erted to its hv drochloπde salt with methanol and ethereal HCI This material is purified bv cry stallization to afford a sample of Formula XXIII B In a similar manner other analogs of Formula XXI II mav be pr epar ed using alternativ e diam o linker molecules Othei compounds indicated as sy nthesized by method D may also be prepared in this manner Example 6 Preparation of a compound of Formula XXIY via method E. Intermediate 4 Intermediate 5 + Example of Formula XXIV Method E A. A solution of 25 mmols of intermediate 4 as prepared in Example 5 is treated with 25 mmols of Synthon E and the mixture acidified to pH 3-4 with cone. HCI and refluxed for two hours. The reaction is concentrated and the residue converted to its hydrochloride salt with methanol and ethereal HCI. This material is purified by crystallization to afford a sample of intermediate 5. A solution of 10 mmols of intennediate 5 and 10 mmols of Synthon F m 5π mL of methanol is acidified to pH 3-4 with cone. F1C1 and the reaction refluxed fo two hr. The reaction is concentrated and the residue converted to its hydrochloride salt with methanol and ethereal HCI. This material is purified by cry stallization to afford a sample of Formula XXIY. B In a similar manner other analogs of Formula XXI\ mav be prepared using alternative diammo linker molecules Other compounds indicated as synthesized by method E may also be prepared in this manner Example 7 Preparation of S\ nthon K\ HO- -Br E -2 0 / DHP / POCI 3 THPO-\^ Br 0 NHCCF 3. 1. LDA THPO. S NH 2 - THPO-^ -Br Synthon K 3. NaOH The THP ether of 2-bromoethanol is prepaied in the usual manner in cthei using phosphorus oxv chloride as the catalv st A solution of V ethv ltπfluoroacetamide in THF is cooled to -30 C and an equiv alent of LD \ THF is added After 30 mm an equiv alent of the abov e THP is added and the reaction armed as necessary W hen complete and equivalent of 1 _\ \aOFl i added and the mixture w armed to complete hv drolv is The i caction is concentrated and worked up in the usual av w ith isopropv 1 acetate and sat sodium bicarbonate to afford Sv nthon K Exan.pl≤_8 Preparation of a compound of Formula \\\ III via method F. Example of Formula XXVII! Method F A. A solution of 30 mmols of the trifluoroacetamide of Synthon G (see prev ions TFAA preparations) in 50 mL of THF is cooled to -30C and an equiv alent of LDA in THF is added. After 30 min., 15 mmols of 1.5-dibromopentane is added and the reaction warmed as necessary-. When complete, an equivalent of 1 X NaOH is added and the mixture wanned to complete hydrolysis. The reaction is concentrated and worked up in the usual way with isopropv 1 acetate and sat. sodium bicarbonate to afford material of Formula XXYIII w hich is purified bv chromatography or crystallization. B. In a similar manner other analogs of Formula XXYIII mav be prepared using alternative dihalo linker molecules. Other compounds indicated as synthesized bv method F may also be prepared in this manner. Preparation of a compound of Formula XXIX v ia method A. A. A mixture of 50 mmols of Synthon H. 25 mmols of bis-2-chloroethv l ether and 50 mmols of potassium carbonate in 20 mL of DMF is w anned as necessary and the reaction followed bv TLC When judged complete, it is partitioned between isopropyl acetate and w ater and the aqueous phase back extracted w uh isopropyl acetate. The combined organic extracts are ashed 3X w ith w ater, dried over sodium sulfate. filtered and the solvent removed ... vacuo to afford material of Formula XXIX. B. In a similar manner other analogs of Formula XXIX may be prepared using alternative dihalo linker molecules. Other compounds indicated as synthesized by method A may also be prepared in this manner. Example 10 Preparation of a compound of Formula XXX via method C. Intermediate 6 4. Synthon H A. A solution of 50 mmols of the trifluoroacetamide of Synthon G 111 l m i mL ι>f THF is cooled to -30C and 5< ) mL of 1 X LDA in THF added After ? ( ) mm 5' > mmols of 1 ,4-dibromobutane is added and the reaction w armed to room temp, and heated further if necessary. When judged complete, it is concentrated and partitioned between isopropyl acetate and water and the aqueous phase back extracted with isopropyl acetate. The combined organic extracts are w ashed 3X with water, dried over sodium sulfate. filtered and the solv ent removed m \ at uo to afford intermediate 6. A mixture of 30 mmols of intermediate 6. 30 mmols of Synthon H and 30 mmols of potassium carbonate in 20 mL of DMF is warmed as necessary and the reaction followed by TLC. When judged complete, it is partitioned between isopropyl acetate and water and the aqueous phase back extracted w ith isopropyl acetate. The combined organic extracts are washed 3X with w ater, dried over sodium sulfate, filtered and the solvent removed /// vacuo. The residue is dissolv ed in 30 mL of methanol and 30 mL of 1_X NaOH added. When hydrolysis is complete, the reaction is concentrated in vacuo and the residue worked up w ith ethyl acetate water. The crude product is purified by chromatography or crystallization to afford material of Fonnula XXX. B. In a similar manner other analogs of Fonnula XXX mav- be prepared using alternative dihalo linker molecules. Other compounds indicated as synthesized bv method C may also be prepared in this manner. E.xample 1 L Preparation of a compound of Formula XXXIII via method F. A A solution of 30 mmols of the tπfluoroacetanude of Svnthon I (see prov ions TFAA preparations) m 50 mL of THF is cooled to -30C and an equiv lent ot LDA in THF is added After 30 nun 15 mmols of 1 ,5-dibromopentane is added and the reaction warmed as necessary When complete, and equiv alent of 1 X NaOH i added and the mixture warmed to complete hydrol sis The reaction is concentrated and worked up in the usual vvav ith isopropv 1 acetate and sat sodrum bicarbonate to afford material of Formula XXXIII B. In a similar manner other analogs of Formula XXXIII may- be prepared usiiu alternative dihalo linker molecules. Other compounds indicated as sy nthesized bv method F may also be prepared in this manner. Example 12 Preparation of a compound of Formula LXYI via method C / K. A. A mixture of 30 mmols of intermediate 3. 30 mmols of Sv nthon K " and 3< ) mmols of potassium carbonate in 20 mL of DMF is wanned as necessar y - and the reaction followed by TLC. When judged complete, it is partitioned between isopropyl acetate and water and the aqueous phase back extracted with isopropv 1 acetate. The combined organic extracts are washed 3X with water, dried over- sodium sulfate, filtered and the solvent removed in vacuo. The residue is dissolv ed in 30 mL of THF and a few drops of cone. HCI added. When THP cleavage is complete, the reaction is concentrated in vacuo and the residue worked up with ethv l acetate and sat. sodium bicarbonate. The crude product is purified by chromatography or crystallization to afford the aiuino-alcohol inteimediate. A solution of 20 mmols of the above intermediate in 20 mL of THF is treated with 25 mmols of o-ethoxyphenylisocv anate and the reaction w armed as necessar y and followed by TLC. When complete, 20 mmols o f 1 X NaOH is added and the hydrolysis is followed to completion. The mixture is concentrated and w orked up m the usual way with ethyl acetate and water lo give material of Formula LXY1 w hich is purified by chromatography- or chromatography-. B. In a similar manner other analogs o f Formula LXYI mav- be prepared using alternative dihalo linker molecules. Other compounds indicated as synthesized bv method C ' K may also be prepared in this manner. Examp ____3 Preparation of a compound of Formula I XIX. Formula LXIX A. A sample of the acid corresponding to Synthon FI is prepared by simple hydrolysis of Synthon H and is conv erted to its trifluoroacetic anhydride in TFIF with TFAA and triethylamine in the usual manner. To the TFIF solution of the anhydride is added 0.5 equivalents of 3,3 , -diamino-N-methyldipiOpylamme. The reaction is warmed as necessary and when complete is concentrated and the residue worked up in the usual manner vv ith isopropv 1 acetate and water to afford material o Formula LXIX which mav- be purified by chromatography- or cry stallization. B. In a similar manner other symmetrical bis amide analogs of Formula LXIX may be prepared using other diamine linker molecules. Preparation of a compound of Formula LXXIII. See Clark, R., et.al. Bioorg. & Med. Chem. Lett., 1994, 4, 2477 for preparation of this type of halo-alkyl ketones Formula LXXIII A. The chloroalkyl aryl ketones indicated in charts F and L are prepared according to the cited references. The chloroethvl ketone is dissolved in THF and I equivalent of triethylamine and 0.5 equivalents of piperidine added and the reaction heated to reflux. When complete, it is concentrated and w orked up with ethv I acetate and sat. sodium bicarbonate in the usual way to afford material of Fonnula LXXIII which is purified by chromatography- or crystallization. B. In a similar manner, analogs of Fonnula LXXIII mav be prepared using oth- diamine linker molecules.

Claims: WHAT IS CLAIMED IS: 1 A multibinding compound comprising from 2 to 1 ligands cov alentlv attached to one or more linkers w herein each of said ligands independently comprises an agonist, partial agonist inv erse agonist or antagonist of the sH ϊ ^ receptors, and pharmaceutically-acceptable salts thereof 2 A multib dmg compound of fonnula 1 ( L U X ) w herein each L is independently a ligand w hich is an agonist partial agonist inverse agonist or antagonist of the 5HT ^ 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 phannaceuticallv -acceptable salts thereof 3 The multibinding compound of C laim 2 w her ein ./ is less than /' 4 The multibmdmg compound of Claim 3 w herein each ligand is independently selected from a compound of fonnula I A IB or IC Ar'-D-E-F IB IC ~ιr~ wherein Rl and R2 are, independently H, alkv 1, substituted alkv 1, a direct link to the linker, or Rl and R2 together fonn a carbocyclic or heterocvclic ring, R3 is H, alkyl, substituted alkvl. alkoxv, a direct link to the linker, or R2 and 5 R3 together fonn a carbocyclic or heterocvclic ring, R4 is N(R),, where Rl is H. alkvl. substituted alkvl, arvl. oi a direct link to the linker, R5 is H, alkoxv, O-alkenvl, O-substituted alkvl or -OC(0)Rl or a direct link to the linker, 10 R6 is H, alkvl. substituted alkvl aivl oi a direct link to the hnkei R7 is H, alkvl, substituted alkvl atv 1 oi a direct link to the hnkei or R4-C=N-R7 fonn a ring selected from the group consisting of 5 oi 6 membered heteroaryl and heterocvclic rings optionally substituted with one to substituents or one or more direct links to linker molecules vv here the substituent is 5 preferably an alkyl sulfonamide group, Drs-C(O)-, -SO -orS E is NR.0 S alkvl or substituted alkv 1 F is alkyl, substituted alk l. alkvl-heterocvchc, alkvl-subsutuled heterocvclic heterocyclic or a direct link to the linker 0 with the proviso that there is at least one direct link to a linker molecule 5 The multibmdmg compound of Claim 4 wherein the ligands are ot formula IA 5 6 The multibinding compound of Claim 4 wheiein the ligands aie ot formula IB 7 The multib dmg compound of Claim 4 where the hgands aie oi formula IC 8 The multib dmg compound of Claim 4 where each hnkei independently has the formula -X a -Z-(Y- , -Z), r Y b -Z-X J - wherein in is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(O)-, -C(O)O-, -C(0)NR-. -C(S). -C(S)0-, -C(S)NR- or a cov alent 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. alkenv lene. substituted alkenylene, alkynylene. substituted alkynylene. cy cloalkenylene. substituted cycloalkenylene. arylene. heteroarylene. heterocyclene. or a cov alent bond; Y a and Y at each separate occurrence are selected from the group consisting of -C(0)NR'-, -NR'C(O)-. -NR (0)NR--, -C(=NR ' )-NR ' -. -NR " -C(=NR , -NR , -C(0)-0-, -N=C( X J )-NR " -, -P(0)( OR " )-0-. -S(0) n CR'R"-. -Sf O^-NR'-. -S-S- and a covalent bond; where /_ is 0. 1 or 2; and R, R' and R" at each separate occuπence are selected from the group consisting o\ hydrogen, alkyl, substituted alkyl. cvcloalkv l, substituted cycloalkyl. alkenv l. substituted alkenyl. cycloalkenyl. substituted cy cloalkenyl. alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. A multibinding compound of formula II: L - X - L " 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: an pharmaceutically-acceptable salts thereof. 10. The multibinding compound of Claim 9 wherein each ligand is independently selected from the group consisting of compounds of formula 1 A- 1 11. The multibinding compound of Claim 10 herem X " has the formula -X'-Z-.Y'-Zl.-V ' -Z-X - wherein 5 m is an integer of from 0 to 20. X a at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-. -C(O)-, -C(O)O-. -C(O)NR-. -C(S). -C(S)0-. -C(S)NR- or a cm alent bond where R is as defined below : Z is at each separate occurrence is selected from the group consisting o\ l ( ι alkylene. substituted alkv lene. cvcloalkvlcne. substituted cv Icoalkv lene. alkenvieue substituted alkenvlene. alkv nv lene. substituted alkv nv lene. eveioalkeiiv lene. substituted cycloalkenylene. arvlene. heteroarvlene. heterocvclene. or a covalent bond; Y J and Y b at each separate occurrence are selected from the group consisting 5 of-C(O)XR ' -. -NR ' C(O)-. -\R ' C(O)\R " -. -Cι=\R ' )-\R ' -. -NR ' -C(=\ ' R . -\R " -C(O)-O-. -N- C(X )-NR " -. -P( ( ))(OR ' )- () -. -S(0),CR ' R"-, -S( ) -N ' R ' -. -_vS- and a covalent bond: where >: is o. i oi 1. and R. R ' and R" at each separate occurrence are selected from the group consisting ol hydrogen, alkyl. substituted alkvl. cvcloalkvl. substituted cvcloalkvl. alkenvl. 0 substituted alkenyl. cycloalkenyl. substituted cycloalkenvl. alkvnvl. substituted alkynyl. aryl. heteroaryl and heterocyclic. 12. A multibmdmg compound of claim 9 wherein the ligand is selected from the group consisting of: 13. The multibinding compound of Claim 12 wherein X" has the formula: -X'-Z-(Y'-Z)„-YAZ-X-- wherein in is an integer of from 0 to 20; X α at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(O)-. -C(0)0-, -C(0)NR-. -C(S). -C(S)0-, -C(S)NR- or a cov lent bond where R is as defined below: Z is at each separate occurrence is selected from the group consisting of alkylene. substituted alkylene. cvcloalkv lene. substituted cv Icoalkv lene. alkenvlene. substituted alkenylene. alkynylene. substituted alkynylene. cvcloalkenv lene. substituted cycloalkenylene. aryleπe. heteroarylene, hetcrocvclenc. or a cov lent bond; Y J and Y" at each separate occurrence are selected from the group consisting of-C(O)NR ' -, -NR " C(OK -NR ' OO.NR " -. -C(=-NR * )-NR ' -. -NR ' -C(=NR . -NR ' -C.O.-O-. -N-C(X )-NR ' -. -P(O)(OR ' )- -. -S(O) n CR'R"-, -S(O) n -NR ' -. -S-S- and a covalent bond; where /; is 0, 1 or 2: and R. R' and R ' ' at each separate occuπence are selected from the group consisting of hydrogen, alkyl. substituted alkyl. cvcloalkvl. substituted cycloalkyl. alkenvl. substituted alkenyl. cycloalkenyl. substituted cycloalkenvl. alkynyl. substituted alkynyl. aryl. heteroaryl and heterocyclic. 14. A multibinding compound of claim 9 wherein the ligand is an agonist. partial agonist, or inverse agonist of the 5HT . , receptors. 15. A multibinding compound of claim 9 where the ligand is aι. antagonist of the 5HT^ receptors. 16. A pharmaceutical composition comprising a pharmaceuticall y acceptable carrier and an effective amount of a multibinding compound comprising from 2 to 10 ligands covalentlv attached to one or more linkers wherein each of said hgands independently compπses an agonist, partial agonist, veise agonist oi antagonist of the 5HT ^ receptois. and phannaceuticallv -acceptable salts thereol 1 7 A phaimaceutical compos'tions comprising a pharmaceuticall y acceptable earner and an effective amount of a multibinding compound of loimula 1 (L)(X) 1 wherein each L is independently a hgand compiisin an agonist partial agonist, inverse agonist oi antagonist of the 5F1T. receptois each X is mdepαui i'iv a linker, p is an integer of from 2 to 1 . and _ / is an mtegei ol tiom 1 to 20 and phannaceuticallv -acceptable salts thereof 18 The pharmaceutical composition ol C hum 1 whet em q is less than /' 19 The pharmaceutical composition ot C hum I whcic ca i hgand i independently selected trom a coruDOund ol formula I A. IB ot IC 20 The phannaceutical composition ot Claim 1 " wherem the hganu is an agonist of the 5HT, leceptors 21 The phaimaceutical composition ot Claim 1 " wheiein the ligand is a partial agonist or inverse agonist of the 5HT_ leceptors 22 The phannaceutical composition of C hum 1 " wheiein the iΛ vi - a' antagonist ot the 5H f_ receptoi 23 The phannaceutical composition of Claim 1 " wherem each hnkei independently has the formula -X-Z-iY -Z) -Z-X wherem m is an integer of from 0 to 20: X a at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(O)-. -C(O)O-_ -C(0)NR-. -C(S). -C(S)O-. -C(S)NR- or a covalent bond where R is as defined below : Z is at each separate occuπence is selected from the group consisting of alkylene, substituted alkylene. cycloalkylene. substituted cylcoalkylcne. alken lene. substituted alkenylene. alkynylene. substituted alkynylene. eveioalkeiiv lene. substituted cycloalkenylene, arylenc. heteroarylene. heteroc clene. 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(0,NR " -. -C(=NR ' )-\ ' R ' -. -NR'-C(=NR , -NR ' -QOl-O-, -N=C(X ' .-XR--. -P(0)(OR ' )-0-, -S(O) n CR'R"-, -S(0),.-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 ol hydrogen, alkyl. substituted alkvl. cycloalky 1. substituted cvcloalkvl. alkenyl. substituted alkenyl. cycloalkenyl. substituted cycloalkenyl. alkynyl. substituted alkynyl, aryl. heteroaryl and heterocyclic. 24. A pharmaceutical compositions compπsing a phannaceuticallv acceptable canier and an effective amount of a multibinding compound of formula II: L ' -X-L " 11 wherein each L ' is independently a hgand comprising an agonist, partial agonist, inverse agonist or antagonist of the 5F1T. receptors: and X ' is a linker ai : phannaceutically-acceptable salts thereof. 25. The phannaceutical composition of Claim 24 wherein each hgand is independently selected from the group consisting of compounds of formulas 1 A-C 26. The phaimaceutical composition of Claim 24 wherem X ' has the formula: -X ' -Z-(Y--Z)..-Y ', -Z-X-- wherein in is an integer of from 0 to 20; X a at each separate occurrence is selected from the group consisting of -0-, -S-. -NR-. -C(O)-. -C(O)O-. -C(O)NR-. -C(S). -C(S)0-. -C(S)NR- or a cov lent bond where R is as defined below ; Z is at each separate occurrence is selected from the group consisting o\ alkylene. substituted alkylene. cvcloalkvlene. substituted cylcoalkylcne. alkcnyiciu. substituted alkenylene. alkynylene. substituted alkynylene. cycloalkenylene. substituted cycloalkenylene. arvlene, heteroarvlene. heterocyclene. or a covalent bond; Y " and Y " at each separate occurrence are selected from the group consistiu-. of-C(0)NR " -. -NR " C(0)-.-NR ' C(0)NR " -. -Ci -NR " ι-\R " -. -NR"-C(=NR . -NR " -C(0)-0-. -N=C(X )-NR ' -. -P(0)(OR " )-0-. -S(0) n CR , R"-. -S(0),-NR ' -. -S-S- and a covalent bond: where // 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. cycloalky 1. substituted cv cloalky 1. alkeny 1. substituted alkenyl. cycloalkenyl. substituted cycloalkenyl. alkynyl. substituted alkynyl. aryl. heteroaryl and heterocyclic. 27. The phannaceutical composition of claim 24. wherein the ligand i . selected from the group consisting of -ι: and 28. The pharmaceutical composition of Claim 27 w herem X" has the formula: -X a -Z-(Y a -Z) m -Y--Z-X J - wherein in is an integer of from 0 to 20: X a at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(O)-. -C(0)0-. -C(0)NR-. -C(S). -C(S)0-. -C(S)NR- or a cov alent 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. alkeny lene. substituted alkenylene, alkynylene, substituted alkynylene. cycloalkenylene. substituted cycloalkenylene, arvlene, heteroaryl ene, heterocyclene, or a cov alent bond; Y and Y h at each separate occunence are selected from the group consisting of -C(0)XR\ -NRT(O)-, -NR-C(O.N ' R--. -C(=NR3-NR " -. -NR'-C(-NR')-, -NR'-C(0)-0-. -N=C(X a )-NR"-. -P(0)(OR 0-. -S(O) n CR'R"-, -S(0) 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 o\ hydrogen, alkyl, substituted alkyl. cycloalkyl. substituted cycloalkyl. alkenyl. substituted alkenyl, cycloalkenyl, substituted cycloalkenyl. alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic. 29. A method for identifying multimeric ligand compounds possessing multibinding properties which method comprises: (a) identifying a ligand or a mixture of ligands w herem each hgand 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. 30. A method for identifying multimeric ligand compounds possessing multibinding properties which method comprises: (a) identifying a library of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) w ith 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. 31. The method according to Claim 29 or 30 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). 32. The method according to Claim 31 wherein the multimeric ligand compounds comprising the multimeric ligand compound library are dimeric. 33. The method according to Claim 32 wherein the dimeric ligand compounds comprising the dimeric ligand compound library are heteromeric. 34. The method according to Claim 33 wherein the heteromeric ligand compound library is prepared by sequential addition of a first and second ligand. 35. The method according to Claim 29 or 30 wherein, prior to procedure (d), each member of the multimeric ligand compound library is isolated from the library. 36. The method according to Claim 35 wherein each member of the library- is isolated by preparative liquid chromatography mass spectrometry (LCMS). 37. The method according to Claim 29 or 30 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. 38. The method according to Claim 37 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups. 39. The method according to Claim 38 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100A. 40. The method according to Claim 29 or 30 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands. 41. The method according to Claim 40 wherein said reactive functionality- is selected from the group consisting of carboxylic acids, carboxylic acid halides. carboxyl esters, amines, halides. pseudohalides. isocyanates, vinyl unsaturation. ketones, aldehydes, thiols, alcohols, anhydπdes, boronates, and precursors thereof wherein the reactiv e functionality on the ligand is selected to be complementary to at least one of the reactiv e groups on the linker so that a cov alent linkage can be formed between the linker and the hgand 42 The method according to Claim 29 or 30 w herein the multnuei IC ligand compound library compπses homomeπc ligand compounds 43 The method according to Claim 29 or 30 w herein the multnuei rc ligand compound library comprises heteromeric ligand compounds 44 A library of multimeπc ligand compounds which may possess multivalent properties which library is prepared by the method compπsing (a) identifying a ligand or a mixture of ligands w herein each hgand contains at least one reactiv e functionality (b) identifying a library of linkers w herein each linker in said hbtaiv compπses at least two functronal groups hav ing complementary reactiv ity to at least one of the reactive functional groups of the ligand, and (c) preparing a multimeπc ligand compound library by combining at least two stoichiometric equiv alents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions herein the complementary functional groups react to form a cov alent linkage between said linker and at least two of said ligands 45 A library of multimeπc ligand compounds which may possess multiv alent properties which library is prepared by the method comprising (a) identifying a library of ligands w herein each hgand contains at least one reactive functionality. (b) identifying a linker or mixture of linkers w herein each linker comprises at least two functional groups hav ing complementary reactiv itv 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. 46. The library according to Claim 44 or 45 wherein the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers. hydrophobic linkers, hydrophilic linkers, linkers of differc _t geometry, acidic linkers, basic linkers, linkers of different polarization and or polarizability and amphiphilic linkers. 47. The library according to Claim 46 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups. 48. The library according to Claim 47 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100A. 49. The library according to Claim 44 or 45 wherein the ligand or mixture of ligands is selected to have reactive functionahtv at different sites on said ligands. 50. The library according to Claim 49 wherein said reactive functionality- is selected from the group consisting of carboxylic acids, carboxylic acid halides. carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation. ketones, aldehydes, thiols, alcohols, anhydrides, boronates. and precursors thereof wherein the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand. 51. The library according to Claim 45 or 46 wherein the multimeπc ligand compound library comprises homomeric ligand compounds. 52. The library according to Claim 44 or 45 wherein the multimeric ligand compound library comprises heteromeric ligand compounds. 53. An iterative method for identifying multimeric ligand compounds possessing multibinding properties which method comprises: (a) preparing a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which target a receptor with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions w herein 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: (0 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. 54 The method according to Claim 53 w herein steps (e) and (f) are repeated from 2-50 times 55 The method according to Claim 53 w herein steps (e) and ( 0 are repeated from 5-50 times 56 A method for treating gastrointestinal disorders comprising admimsteπng to a patient in need thereof an effectiv e amount of a compound ol claim 1 to treat the disorder 57 The method of claim 56, wherem the gastrointestinal disorder is selected from the group consisting of reflux esophagitis. gastroesophageal reflux disorder (GERD), Barrett syndrome, intestinal pseudoileus. acute or chronic gastπtis, gastπc or duodenal ulcer, Crohn's disease, non-ulcer d spepsia. gastroparesis, functional d spepsia, ulcerativ e colitis, postgastiectomy syndrome postoperativ e digestiv e function failure, delay ed gastric empty ing caused by gastr ic neurosis, gastroptosis or diabetes, gastrointestinal disorders, and irritable bowel syndrome 58 The method of claim 56, wherein the gastrointestinal disorder is selected from the group consisting of indigestion, meteorism, abdominal indefinite complaint, atonic constipation, chronic constipation and constipation caused by spinal cord injury or pelvic diaphragm failure 59 The method of claim 56. wherein the compound is a compound according to claim 2 60 The method of claim 56, wherein the compound is a compound according to claim 4 61 A method for treating central nerv ous disorders comprising — I JJ — administering to a patient in need thereof an effective amount of a compound of claim 1 to treat the disorder. 62. The method of claim 61 , wherein the central nervous disorder is selected from the group consisting of schizophrenia, depression, anxiety, disturbance of memory and dementia. 63. The method of claim 61. wherein the compound is a compound according to claim 2. 64. The method of claim 61, wherein the compound is a compound according to claim 4. 65. A method for treating cardiac function disorders comprising administering to a patient in need thereof an effective amount of a compound of claim 1 to treat the disorder. 66. The method of claim 65. wherein the cardiac function disorder is selected from the group consisting of cardiac failure and myocardial ischemia. 67. The method of claim 65. wherein the compound is a compound according to claim 2. 68. The method of claim 65, wherein the compound is a compound according to claim 4. 69. A method for treating urinary disorders comprising administering to a patient in need thereof an effective amount of a compound of claim 1 to treat the disorder. 70. The method of claim 69, wherein the urinary disorder is selected from the group consisting of dvsuria caused by urinary obstniction. ureterohth, prostatomegaly, spinal cord injury, and pelvic diaphragm failure. 71. The method of claim 69, wherein the compound is a compound according to claim 2. 72. The method of claim 69. wherein the compound is a compound according to claim 4.

Inventors: GRIFFIN JOHN H, NATARAJAN MAYA, GRIFFIN, JOHN, H., NATARAJAN, MAYA
Applicants: ADVANCED MEDICINE INC, GRIFFIN JOHN H, NATARAJAN MAYA, ADVANCED MEDICINE, INC., GRIFFIN, JOHN, H., NATARAJAN, MAYA
Application year: 1999
Main classification: A61K38
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