Pharmaceutical compositions and their methods of use

Abstract

The invention relates to a composition comprising a neuronal nicotinic receptor ligand and an α4β2 positive allosteric modulator, a method of using the same, and a related article of manufacture.

1 . A composition, comprising:
 (i) a nicotinic acetylcholine receptor ligand and   (ii) a nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator in admixture with at least one pharmaceutically acceptable excipient.   
     
     
         2 . The composition of  claim 1 , wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α4β2 ligand demonstrating a K i  value that as measured by [ 3 H]-cytisine binding assay (K i  Cyt) of about 0.001 nanomolar to about 100 micromolar. 
     
     
         3 . The composition of  claim 1 , wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α4β2 agonist or partial agonist. 
     
     
         4 . The composition of  claim 1 , wherein the nicotinic acetylcholine receptor ligand is a heterocyclic ether derivative, a N-substituted diazabicyclic derivative, or a heterocyclic substituted amino azacycle compound. 
     
     
         5 . The composition of  claim 1 , wherein the nicotinic acetylcholine receptor ligand is a compound selected from: 
       5-[(2R)-azetidin-2-yl methoxy]-2-chloropyridine, 
       (3R)-1-pyridin-3-ylpyrrolidin-3-amine, and 
       2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 
       3-(5,6-dichloro-pyridin-3-yl)-1(S),5(S)-3,6-diazabicyclo[3.2.0]heptane; and 
       (R,R)-1-(pyridin-3-yl)octahydro-pyrrolo[3,4-b]pyrrole;
 or is a pharmaceutically acceptable salt thereof. 
 
     
     
         6 . The composition of  claim 1 , wherein the nicotinic acetylcholine receptor ligand is selected from aryl-fused azapolycyclic compounds, aryl-substituted olefinic amine compounds, pyridopyranoazepine derivatives, benzylidene- and cinnamylidene-anabaseines, and 3-pyridoxylalkyl heterocyclic ether compounds. 
     
     
         7 . The compound of  claim 6 , wherein the nicotinic acetylcholine receptor ligand is selected from the group consisting of: 
       5-[(2R)-azetidin-2-yl methoxy]-2-chloropyridine; 
       (3R)-1-pyridin-3-ylpyrrolidin-3-amine; 
       2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine; 
       3-(5,6-dichloro-pyridin-3-yl)-1S,5S-3,6-diazabicyclo[3.2.0]heptane; 
       (R,R)-1-(pyridin-3-yl)octahydro-pyrrolo[3,4-b]pyrrole; 
       6,10-methano-6H-pyrazino[2,3-h][3]benzazepine; 
       7,8,9,10-tetrahydro-(2S,4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine; 
       (2S,4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine; 
       (2S,4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine; 
       (2S,4E)-N-methyl-3-pyrimidine-4-penten-2-amine;
 (5aS,8S,10aR)-5a,6,9,10-tetrahydro-7H,11H-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine; 
 
       3-[1-(2,4-dimethoxy-phenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl; and 
       3-[1-(2-methoxy-4-hydroxyphenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;
 or is a pharmaceutically acceptable salt thereof. 
 
     
     
         8 . The composition of  claim 1 , wherein the nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator has a formula: 
       
         
           
           
               
               
           
         
         or is a pharmaceutically acceptable salt or prodrug thereof, wherein 
         X is a bond, O, NR 1 , S, or C 1 -C 3  alkylene; 
         Y represents a monocyclic aryl, cycloalkyl, heterocycle, or heteroaryl group; 
         Ar 1  represents a monocyclic aryl or heteroaryl group; and 
         R 1  is hydrogen, alkyl, haloalkyl or arylalkyl. 
       
     
     
         9 . The composition of  claim 1 , wherein the nicotinic subtype α4β2 positive allosteric modulator has the formula: 
       
         
           
           
               
               
           
         
         or is a pharmaceutically acceptable salt thereof, wherein 
         Ar 2  is monocyclic aryl or monocyclic heteroaryl, wherein the aryl or heteroaryl is substituted or unsubstituted, and, when substituted, the aryl or heteroaryl is substituted with 1, 2, 3, or 4 substituents selected from halo, C 1 -C 6  haloalkyl, C 6 -C 10  aryl, C 4 -C 7  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 5 -C 10  heteroaryl, C 4 -C 10  heterocycle, C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)NHC(O)O—(C 1 -C 6  alkyl), C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkylcarbonyl, amino, hydroxyl, haloalkyl-C(O)—, haloalkyl-SO 2 —, alkyl-SO 2 —, —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , cyano, nitro, C 1 -C 6  acylamino, C 1 -C 6  alkoxy, —C(O)NH 2 , —C(O)O—(C 1 -C 6  alkyl), and carboxy; and 
         Ar 3  is monocyclic aryl or monocyclic heteroaryl, wherein the aryl or heteroaryl is substituted or unsubstituted, and, when substituted, the aryl or heteroaryl is substituted with a substituent selected from halo, C 1 -C 6  haloalkyl, C 6 -C 10  aryl, C 4 -C 7  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 5 -C 10  heteroaryl, C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, amino, hydroxyl, haloalkyl-SO 2 —, cyano, nitro, C 1 -C 6  acylamino, C 1 -C 6  alkoxy, —N(C 1 -C 6  alkyl) 2 , and carboxy. 
       
     
     
         10 . The composition of  claim 1 , wherein the nicotinic subtype α4β2 positive allosteric modulator is a compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein Ar 2  is substituted, pyridinyl, unsubstituted pyridinyl, or substituted phenyl; and Ar 3  is substituted pyridinyl, unsubstituted pyridinyl or substituted phenyl; wherein the pyridinyl group, when substituted, is substituted with fluoro and the phenyl group is substituted with cyano, sulfonamide or fluoro. 
     
     
         11 . The composition of  claim 10 , wherein Ar 2  is cyanophenyl and Ar 3  is pyridin-3-yl. 
     
     
         12 . The composition of  claim 1 , wherein the nicotinic subtype α4β2 positive allosteric modulator is selected from: 
       3,5-diphenylisoxazole; 
       3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; 
       3,5-di(pyridin-3-yl)-1,2,4-oxadiazole; 
       3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile; 
       3-(5-(6-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile; 
       5-(5-bromopyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       3-(pyridin-3-yl)-5-(3-(trifluoromethylsulfonyl)phenyl)-1,2,4-oxadiazole; 
       3-(3-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; 
       5-(5-(pyrrol-1-yl)pyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-3-ol; 
       5-(3,4-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(2,3-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(pyrazin-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(3,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(2,3,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(2,4,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(4-chloro-2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(5-methylpyrazin-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; 
       2,3,6-trifluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol; 
       2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol; 
       2-fluoro-4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol; 
       5-(3-chloro-4-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(3,4-dichlorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       2-nitro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol; 
       5-(2,3,6-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       2,2,2-trifluoro-1-(4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanone; 
       5-(3-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(4-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(2-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       3-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; 
       3-(2,3-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole; 
       3-(3,4-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(2,6-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide; 
       5-(2,4-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(2,3,4-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(3,4,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(4-chloro-3-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(3-nitrophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(3-(methylsulfonyl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       3-(2-chloropyridin-4-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole; 
       3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzamide; 
       4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one; 
       tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzoate; 
       2-amino-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol; 
       N,N-dimethyl-4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine; 
       3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzoic acid; 
       5-(3-(1H-tetrazol-5-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       N,N-diethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide; 
       2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; 
       3-(3-(1H-tetrazol-5-yl)phenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole; 
       3-(6-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(6-chloropyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one; 
       5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one; 
       N-methyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide; 
       3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)aniline; 
       (3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine; 
       5-(2-chloropyridin-4-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one; 
       tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzylcarbamate; 
       5-(3-bromophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidin-2-one; 
       tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenylcarbamate; 
       N,N-dimethyl-1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine; 
       5-(3-(piperazin-1-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanone; 
       3-(6-chloropyridin-3-yl)-5-(2,3-difluorophenyl)-1,2,4-oxadiazole; 
       3-(6-chloropyridin-3-yl)-5-(3,4-difluorophenyl)-1,2,4-oxadiazole; 
       (R)-3-(pyridin-3-yl)-5-(3-(pyrrolidin-2-yl)phenyl)-1,2,4-oxadiazole; 
       5-(3-(1H-pyrazol-3-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole; 
       1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanol; 
       3-(3-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; 
       3-(4-fluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole; 
       3-(5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile; 
       3-(5-(2-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile; 
       3-fluoro-5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile; 
       2,5-di(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(5-bromopyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(pyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazole; 
       2-(pyridin-3-yl)-5-o-tolyl-1,3,4-oxadiazole; 
       2-(pyridin-3-yl)-5-m-tolyl-1,3,4-oxadiazole; 
       2-(pyridin-3-yl)-5-p-tolyl-1,3,4-oxadiazole; 
       2-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol; 
       3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol; 
       4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol; 
       2-(3-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-fluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3-fluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-fluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-bromophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3-bromophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-bromophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)benzonitrile; 
       4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)benzonitrile; 
       N,N-dimethyl-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline; 
       N,N-dimethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline; 
       2-(pyridin-3-yl)-5-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole; 
       2-(pyridin-3-yl)-5-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole; 
       2-(4-phenoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-(benzyloxy)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3,4-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,4-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3,4-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,3-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,4-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,5-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,4-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3,5-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(pyridin-3-yl)-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazole; 
       2-(3,4-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,4-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,5-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3,4-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       5-methyl-2-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol; 
       2-methyl-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol; 
       2-(3-fluoro-2-methyl phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(5-fluoro-2-methyl phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3-fluoro-4-methyl phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,3-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,4-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,5-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3,5-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       1-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)ethanone; 
       2-(4-isopropylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3-methoxy-4-methyl phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-ethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-(methylthio)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3-fluoro-4-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(naphthalen-1-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(naphthalen-2-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       4-chloro-2-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol; 
       2-(4-tert-butylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       N-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)acetamide; 
       2-(4-propoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-isopropoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(5-chloro-2-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-fluoronaphthalen-1-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       N,N-diethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline; 
       2-(4-butoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-methoxy-4-(methylthio)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-(methylsulfonyl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-chloro-5-(methylthio)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-chloro-5-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-phenethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-bromo-5-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(5-bromo-2-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-iodophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(3-iodophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(4-iodophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(pyridin-3-yl)-5-(pyrimidin-5-yl)-1,3,4-oxadiazole; 
       2-(5-methylpyrazin-2-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-chloro-6-methylpyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-(ethylthio)pyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,6-dimethoxypyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-(methylthio)pyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       5-chloro-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-ol; 
       2-(2,6-dichloro-5-fluoropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,5-dichloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(6-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2,6-dichloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 
       2-(2-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; and 
       2-(pyridin-3-yl)-5-(quinolin-3-yl)-1,3,4-oxadiazole;
 or is a pharmaceutically acceptable salt thereof. 
 
     
     
         13 . The composition of  claim 1 , wherein the nicotinic subtype α4β2 positive allosteric modulator is a 2,5-disubstituted-1,3,4-oxadiazole derivative; a 3,5-disubstituted-1,2,4-oxadiazole derivative, or 3,5-diphenylisoxazole. 
     
     
         14 . A method for use in treating or preventing pain in a patient, comprising:
 (i) administering an amount of nicotinic subtype α4β2 positive allosteric modulator to the patient; and   (ii) administering a pain medication comprising a compound selected from an opioid, gabapentin, pregabalin, duloxetine, a cannabinoid ligand, a vaniolloid receptor antagonist, calcium channel blocker and a sodium channel blocker wherein a descending modulatory pathway that is shared or commonly activated via the α4β2 nicotinic receptor mechanism is activated.   
     
     
         15 . A method for use in treating or preventing pain, including neuropathic pain and cognitive disorders in a patient, comprising:
 (i) administering an amount of nicotinic acetylcholine receptor ligand to the patient; and   (ii) administering an amount of nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator to the patient; wherein the amounts of (i) and (ii) together are more effective in treating pain or cognitive disorders.   
     
     
         16 . A method for use in treating or preventing a condition or disorder selected from attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-associated memory impairment (AAMI), senile dementia, AIDS dementia, Pick's Disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, schizophrenia, schizoaffective disorder, smoking cessation, amyotrophic lateral sclerosis, Huntington's disease, diminished CNS function associated with traumatic brain injury, infertility, lack of circulation, need for new blood vessel growth associated with wound healing, ischemia, sepsis, inflammation and inflammatory disorders comprising:
 (i) administering an amount of nicotinic acetylcholine receptor ligand to the patient; and   (ii) administering an amount of nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator to the patient; wherein the amounts of (i) and (ii) together are more effective in treating disorders.   
     
     
         17 . A method for use of treating or preventing a condition or disorder characterized by attention or cognitive dysfunction comprising administering a therapeutically effective amount of a nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator to a subject in need thereof in combination with a nicotinic acetylcholine receptor ligand or an acetylcholinesterase inhibitor. 
     
     
         18 . A method of treating or preventing a condition or disorder characterized by neuropsychological dysfunction comprising administering a therapeutically effective amount of a nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator to a subject in need thereof in combination with an antipsychotic agent. 
     
     
         19 . An article of manufacture, comprising:
 (i) a first pharmaceutical dosage form comprising at least one nicotinic acetylcholine receptor ligand; and   (ii) a second pharmaceutical dosage form comprising at least nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator; wherein the article contains first and second pharmaceutical dosage forms.   
     
     
         20 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein Ar 2  is substituted pyridinyl, unsubstituted pyridinyl, or substituted phenyl; and Ar 3  is substituted pyridinyl, unsubstituted pyridinyl, or substituted phenyl; wherein the pyridinyl group, when substituted, is substituted with fluoro and the phenyl group is substituted with cyano, sulfonamide or fluoro. 
     
     
         21 . The compound of  claim 17 , wherein Ar 2  is cyanophenyl and Ar 3  is pyridin-3-yl. 
     
     
         22 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein 
         Ar 2  is monocyclic aryl or monocyclic heteroaryl, wherein the aryl or heteroaryl is substituted or unsubstituted, and, when substituted, the aryl or heteroaryl is substituted with 1, 2, 3, or 4 substituents selected from halo, C 1 -C 6  haloalkyl, C 6 -C 10  aryl, C 4 -C 7  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 5 -C 10  heteroaryl, C 4 -C 10  heterocycle, C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)NHC(O)O—(C 1 -C 6  alkyl), C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkylcarbonyl, amino, hydroxyl, haloalkyl-C(O)—, haloalkyl-SO 2 —, alkyl-SO 2 —, —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , cyano, nitro, C 1 -C 6  acylamino, C 1 -C 6  alkoxy, —C(O)NH 2 , —C(O)O—(C 1 -C 6  alkyl), and carboxy; and 
         Ar 3  is monocyclic aryl or monocyclic heteroaryl, wherein the aryl or heteroaryl is substituted or unsubstituted, and, when substituted, the aryl or heteroaryl is substituted with a substituent selected from halo, C 1 -C 6  haloalkyl, C 6 -C 10  aryl, C 4 -C 7  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 5 -C 10  heteroaryl, C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, amino, hydroxyl, haloalkyl-SO 2 —, cyano, nitro, C 1 -C 6  acylamino, C 1 -C 6  alkoxy, —N(C 1 -C 6  alkyl) 2 , and carboxy; 
         wherein at least one of the available atoms within a compound of formula (II*) is replaced with a radioisotope. 
       
     
     
         23 . A compound that is [ 3 H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile. 
     
     
         24 . Use of a radiolabelled form of a compound of formula (II*) for determining the binding affinity of nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulators.