Methods and compositions for treatment of central nervous system disorders

Abstract

The invention provides methods of screening for substances having an effect on a nicotine receptor by contacting a cell having a nicotine receptor with a test substance; and determining any increase or decrease in phosphorylation of Janus-Activated Kinase 2 (JAK2). An increase in phosphorylation of JAK2 indicates that the test substance stimulates the nicotine receptor, and wherein a decrease in phosphorylation of JAK2 indicates that the test substance inhibits the nicotine receptor. The invention also provides screening methods for identification of substances that affect nicotine receptor activity through activity mediated by the AT2 receptor. Related pharmaceutical compositions and methods of treatment are also provided.

1 . A composition comprising, 
 a) a substance that binds α7 nicotinic acetylcholine receptors (α7-nAChR); and    b) at least one inhibitor of the AT2 receptor or at least one inhibitor of a substance that stimulates the AT2 receptor; and    c) a pharmaceutically acceptable carrier.    
   
   
       2 . The composition of  claim 1 , wherein the substance that binds α7-nAChR is selected from the group consisting of 2-(3-pyridyl)azaadamantanes, diazabicyclic compounds, pyridylazabicyclic compounds, cinnamamides of 3-aminoquinuclidine, arylcarbamates of 3-quinuclidinol, aromatic amides of 3-aminoquinuclidine, spiroquinuclidines, and benzylideneanabaseines.  
   
   
       3 . The composition of  claim 1 , wherein the substance that inhibits the AT2 receptor or that inhibits a substance that stimulates the AT2 receptor is a substance that inhibits a substance that stimulates AT2.  
   
   
       4 . The composition of  claim 1 , wherein the substance that inhibits the AT2 receptor or that inhibits a substance that stimulates the AT2 receptor is a substance that inhibits AT2.  
   
   
       5 . The composition of  claim 1 , wherein the substance that binds α7 nAChR is a 2-(3-pyridyl)azaadamantane compound selected from the group consisting of 
 1-aza-2-(5-bromo(3-pyridyl))tricyclo[3.3.1.1 3,7 ]decane;    1-aza-2-(5-amino-(3-pyridyl))tricyclo[3.3.1.1 3,7 ]decane;    1-aza-2-(5-ethoxy-(3-pyridyl))tricyclo[3.3.1.1 3,7 ]decane;    1-aza-2-(5-isopropoxy-(3-pyridyl))tricyclo[3.3.1.1 3,7 ]decane;    2-(3-pyridyl)-1-azatricyclo[3.3.1.1 3,7 ]decane;    5-aza-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]decan-2-ol;    5-aza-1-(hydroxymethyl)-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]-decan-2-one;    1-aza-2-(3-pyridyl)-1-azatricyclo[3.3.1.1 3,7 ]decane;    5-aza-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]decan-2-ol;    5-aza-1-(hydroxymethyl)-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]-decan-2-one;    5-aza-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]decan-2-one;    enantiomers thereof; and    pharmaceutically acceptable salts thereof.    
   
   
       6 . The composition of  claim 1 , where the substance that binds α7 nAChR is a diazabicyclic compound selected from the group consisting of 
 (1S,4S)-2-(5-phenoxy-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-phenoxy-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(3-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(3-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(4-fluorophenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(4-fluorophenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-benzoyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-benzoyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(4-(N-trifluoroacetylpiperidinyl)oxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(4-(N-trifluoroacetylpiperidinyl)oxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    6-methyl-3-(5-phenyl-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-phenoxy-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(3-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(4-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(4-fluorophenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-benzoyl-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-phenyl-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-phenoxy-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(3-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(4-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(4-fluorophenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-benzoyl-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-(5-phenyl-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-phenoxy-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(3-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(4-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(4-fluorophenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-benzoyl-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-phenyl-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-phenoxy-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(3-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(4-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(4-fluorophenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-benzoyl-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-phenyl-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-phenoxy-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(3-methoxyphenoxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(4-methoxyphenoxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(4-fluorophenoxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-benzoyl-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    enantiomers thereof; and    a pharmaceutically acceptable salt thereof.    
   
   
       7 . The composition of  claim 1 , wherein the substance that binds α7 nAChR is a cinnamamide of 3-aminoquinuclidine selected from the group consisting of 
 N-(1-Azabicyclo[2.2.2]oct-3-yl)(E-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-nitrophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-nitrophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-aminophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[Z-3-(2-methoxyphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)-N-methyl-(E-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-2-phenylcyclopropane-1-carboxamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)(Z-2-fluoro-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-formamidophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-nitrophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)(E-3-(4-aminophenyl)propenamide;    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-formamidophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)(Z-3-methyl-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-N-methylanlinophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-N,N-dimethylaminophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)(Z-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)(E-3-methyl-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)(E-2,3-diphenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-methoxyphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)(E methyl-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-methylphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-methoxyphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-fluorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-fluorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-(2-chlorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-chlorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-chlorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3,4-dichlorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)-[E-3-(3-bromophenyl)propenamide]   N-(1-Azabicyclo[2.2.2]oct-3-yl)-[E-3-(4-bromophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-iodophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-iodophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-trifluoromethylphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)-[E-3-(3-trifluoromethylphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-furyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-furyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-thienyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-thienyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(5-nitro-2-furyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(5-methoxy-3-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(5-hydroxy-3-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-imidazolyl)propenamide];    N-(endo-8-Aza-8-methylbicyclo[3.2.1]oct yl)(E-3-phenylpropenamide);    N-(exo-8-Aza-8-methylbicyclo[3.2.1]oct yl)(E-3-phenylpropenamide);    enantiomers thereof; and    a pharmaceutically acceptable salt thereof.    
   
   
       8 . The composition of  claim 1 , wherein the substance that binds α7 nAChR is an arylcarbamate of 3-quinuclidinol selected from the group consisting of 
 N-phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-bromophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-methylphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(3,4-dichlorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-cyanophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-phenylcarbamic acid 1-azabicyclo[2.2.1]heptan-3-yl ester;    N-(3-methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-phenylthiocarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(2-pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(1-naphthyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-phenylcarbamic acid (3R)-1-azabicyclo[2.2.2]octan-3-yl ester;    N-phenylcarbamic acid (3S)-1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(m-biphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(3-quinolinyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    enantiomers thereof; and    pharmaceutically acceptable salts thereof.    
   
   
       9 . The composition of  claim 1 , wherein the substance that binds α7 nAChR is an aromatic amide of 3-aminoquinuclidine selected from the group consisting of 
 N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-phenylthiophene-2-carboxamide;    N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-phenyl-1,3,4-oxadiazole-2-carboxamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-y-1]-4-(4-hydroxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(-4-acetamidophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-phenoxybenzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-benzylbenzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-phenoxybenzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-benzoylbenzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-fluorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-fluorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-fluorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-chlorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-methoxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-methoxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorophenylsulfanyl)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-methoxyphenylsulfanyl)-benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4(2-methoxyphenylsulfanyl)-benzamide;    N-(2-methyl-1-azabicyclo[2.2.2]oct-3-yl)4-phenoxybenzamide;    enantiomers thereof; and    pharmaceutically acceptable salts thereof.    
   
   
       10 . The composition of  claim 1 , wherein the substance that binds α7 nAChR is a spiroquinuclidines selected from the group consisting of 
 spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    1′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]isoquinoline];    5′-(phenylcarboxamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(phenylaminocarbonylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(phenylsulfonylamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N,N-dimethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N,N-diethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-ethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-benzylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-formamidospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-acetamidospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]isoquinoline];    spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]quinoline];    5′-ethenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(E)-(phenylethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(4-morpholino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(1-azetidinyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(E)-(2-(4-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine;    5′-(E)-(2-(2-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine;    5′-(2-trimethylsilylethynyl(spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine;    5′-ethynylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(2-furyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(3-pyridyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-methylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    spiro[1-azabicyclo[2.2.2]octane-3,2′-3′H)-furo[2,3-b]pyridine-5′carbonitrile];    spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine-5′carboxamide];    5′-N′-(3chlorophenyl)ureidoaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N′-(2-nitrophenyl)ureidoaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′chlorospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-methoxyspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-phenylthiospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-(N-2-aminoethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-phenylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-(4-N-methylpiperazin-1-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine;    4′-chloro-spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[3,2-c]pyridine];    spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[3,2-c]pyridine];    6′-fluorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-6′-carbonitrile];    6′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    enantiomers thereof; and    pharmaceutically acceptable salts thereof.    
   
   
       11 . The composition of  claim 1 , wherein the substance that binds α7 nAChR is a benzylideneanabaseine selected from the group consisting of 
 3-(2,4-dimethoxybenzylidene)anabaseine, 3-(4-hydroxybenzylidene)anabaseine;    3-(4-methoxybenzylidene)anabaseine, 3-(4-aminobenzylidene)anabaseine;    3-(4-hydroxy-2-methoxybenzylidene)anabaseine;    3-(2-hydroxy-4-methoxybenzylidene)anabaseine;    3-(4-isopropoxybenzylidene)anabaseine;    (7′-methyl-3-(2,4dimethoxybenzylidene))anabaseine;    3-(4-acetylaminocinnamylidene)anabaseine;    3-(4-hydroxycinnamylidene)anabaseine;    3-(4-methoxycinnamylidene)anabaseine;    3-(4-hydroxy-2-methoxycinnamylidene)anabaseine;    3-(2,4-dimethoxycinnamylidene)anabaseine; and    3-(4-acetoxycinnamylidene)anabaseine;    enantiomers thereof; and    pharmaceutically acceptable salts thereof.    
   
   
       12 . The composition of  claim 4 , wherein the substance that inhibits AT2 is PD123177 or PD123319.  
   
   
       13 . A composition for reducing apoptosis mediated by a β-amyloid polypeptide in mammalian neurons, comprising, 
 a) a substance that binds α7-nAChR; and    b) at least one inhibitor of the AT2 receptor or at least one inhibitor of a substance that stimulates the AT2 receptor; and    c) a pharmaceutically acceptable carrier.    
   
   
       14 . The composition of  claim 13 , wherein the substance that binds α7-nAChR is selected from the group consisting of 2-(3-pyridyl)azaadamantanes, diazabicyclic compounds, pyridylazabicyclic compounds, cinnamamides of 3-aminoquinuclidine, arylcarbamates of 3-quinuclidinol, aromatic amides of 3-aminoquinuclidine, spiroquinuclidines, and benzylideneanabaseines.  
   
   
       15 . The composition of  claim 13 , wherein the substance that inhibits the AT2 receptor or that inhibits a substance that stimulates the AT2 receptor is a substance that inhibits a substance that stimulates AT2.  
   
   
       16 . The composition of  claim 13 , wherein the substance that inhibits the AT2 receptor or that inhibits a substance that stimulates the AT2 receptor is a substance that inhibits AT2.  
   
   
       17 . The composition of  claim 16 , wherein the substance that inhibits AT2 is PD123177 or PD123319.  
   
   
       18 . The composition of  claim 13 , wherein the substance that binds α7-nAChR is selected from the group consisting of: 
 1-aza-2-(5-bromo(3-pyridyl))tricyclo[3.3.1.1 3,7 ]decane;    1-aza-2-(5-amino-(3-pyridyl))tricyclo[3.3.1.1 3,7 ]decane;    1-aza-2-(5-ethoxy-(3-pyridyl))tricyclo[3.3.1.1 3,7 ]decane;    1-aza-2-(5-isopropoxy-(3-pyridyl))tricyclo[3.3.1.1 3,7 ]decane;    2-(3-pyridyl)-1-azatricyclo[3.3.1.1 3,7 ]decane;    5-aza-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]decan-2-ol;    5-aza-1-(hydroxymethyl)-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]-decan-2-one;    1-aza-2-(3-pyridyl)-1-azatricyclo[3.3.1.1 3,7 ]decane;    5-aza-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]decan-2-ol;    5-aza-1-(hydroxymethyl)-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]-decan-2-one;    5-aza-6-(3-pyridyl)tricyclo[3.3.1.1 3,7 ]decan-2-one;    (1S,4S)-2-(5-phenoxy-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-phenoxy-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(3-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(3-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(4-fluorophenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(4-fluorophenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-benzoyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-benzoyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1S,4S)-2-(5-(4-(N-trifluoroacetylpiperidinyl)oxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    (1R,4R)-2-(5-(4-(N-trifluoroacetylpiperidinyl)oxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane;    6-methyl-3-(5-phenyl-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-phenoxy-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(3-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(4-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(4-fluorophenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-benzoyl-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-methyl-3-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-phenyl-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-phenoxy-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(3-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(4-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(4-fluorophenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-benzoyl-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    3-methyl-6-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,6-diazabicyclo[3.2.1]octane;    6-(5-phenyl-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-phenoxy-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(3-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(4-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(4-fluorophenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-benzoyl-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    6-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-phenyl-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-phenoxy-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(3-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(4-methoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(4-fluorophenoxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-benzoyl-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,6-diazabicyclo[3.2.2]nonane;    3-(5-phenyl-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-phenoxy-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(3-methoxyphenoxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(4-methoxyphenoxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(3,4-dimethoxyphenoxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(4-fluorophenoxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-benzoyl-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    3-(5-(4-(N-phenylpiperidinyl)oxy)-3-pyridyl)-3,7-diazabicyclo[3.3.1]nonane;    N-(1-Azabicyclo[2.2.2]oct-3-yl)(E-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-nitrophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-nitrophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-aminophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[Z-3-(2-methoxyphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)-N-methyl-(E-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-2-phenylcyclopropane-1-carboxamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)(Z-2-fluoro-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-formamidophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-nitrophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)(E-3-(4-aminophenyl)propenamide;    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-formamidophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)(Z-3-methyl-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-N-methylanlinophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-N,N-dimethylaminophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)(Z-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)(E-3-methyl-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)(E-2,3-diphenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-methoxyphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)(E methyl-3-phenylpropenamide);    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-methylphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-methoxyphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-fluorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-fluorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-(2-chlorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-chlorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-chlorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3,4-dichlorophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)-[E-3-(3-bromophenyl)propenamide]   N-(1-Azabicyclo[2.2.2]oct-3-yl)-[E-3-(4-bromophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-iodophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-iodophenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-trifluoromethylphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)-[E-3-(3-trifluoromethylphenyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-furyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-furyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-thienyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(3-thienyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(5-nitro-2-furyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(5-methoxy-3-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(5-hydroxy-3-pyridyl)propenamide];    N-(1-Azabicyclo[2.2.2]oct-3-yl)[E-3-(4-imidazolyl)propenamide];    N-(endo-8-Aza-8-methylbicyclo[3.2.1]oct yl)(E-3-phenylpropenamide);    N-(exo-8-Aza-8-methylbicyclo[3.2.1]oct yl)(E-3-phenylpropenamide);    N-phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-bromophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-methylphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(3,4-dichlorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-cyanophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-phenylcarbamic acid 1-azabicyclo[2.2.1]heptan-3-yl ester;    N-(3-methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-phenylthiocarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(2-pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(1-naphthyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-phenylcarbamic acid (3R)-1-azabicyclo[2.2.2]octan-3-yl ester;    N-phenylcarbamic acid (3S)-1-azabicyclo[2.2.2]octan-3-yl ester;    N-(4-pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(m-biphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-(3-quinolinyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;    N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-phenylthiophene-2-carboxamide;    N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-phenyl-1,3,4-oxadiazole-2-carboxamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-y-1]-4-(4-hydroxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(-4-acetamidophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-phenoxybenzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-benzylbenzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-phenoxybenzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-benzoylbenzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-fluorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-fluorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-fluorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-chlorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorophenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-methoxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-methoxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxyphenoxy)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorophenylsulfanyl)benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-methoxyphenylsulfanyl)-benzamide;    N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4(2-methoxyphenylsulfanyl)-benzamide;    N-(2-methyl-1-azabicyclo[2.2.2]oct-3-yl)4-phenoxybenzamide;    spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    1′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]isoquinoline];    5′-(phenylcarboxamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(phenylaminocarbonylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(phenylsulfonylamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N,N-dimethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N,N-diethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-ethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-benzylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-formamidospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N-acetamidospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]isoquinoline];    spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]quinoline];    5′-ethenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(E)-(phenylethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(4-morpholino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(1-azetidinyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(E)-(2-(4-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine;    5′-(E)-(2-(2-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine;    5′-(2-trimethylsilylethynyl(spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine;    5′-ethynylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-(2-furyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]   5′-(3-pyridyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-methylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    spiro[1-azabicyclo[2.2.2]octane-3,2′-3′H)-furo[2,3-b]pyridine-5′carbonitrile];    spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine-5′carboxamide];    5′-N′-(3chlorophenyl)ureidoaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    5′-N′-(2-nitrophenyl)ureidoaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′chlorospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-methoxyspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-phenylthiospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-(N-2-aminoethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-phenylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    4′-(4-N-methylpiperazin-1-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine;    4′-chloro-spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[3,2-c]pyridine];    spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[3,2-c]pyridine];    6′-fluorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-6′-carbonitrile];    6′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];    3-(2,4-dimethoxybenzylidene)anabaseine, 3-(4-hydroxybenzylidene)anabaseine;    3-(4-methoxybenzylidene)anabaseine, 3-(4-aminobenzylidene)anabaseine;    3-(4-hydroxy-2-methoxybenzylidene)anabaseine;    3-(2-hydroxy-4-methoxybenzylidene)anabaseine;    3-(4-isopropoxybenzylidene)anabaseine;    (7′-methyl-3-(2,4dimethoxybenzylidene))anabaseine;    3-(4-acetylaminocinnamylidene)anabaseine;    3-(4-hydroxycinnamylidene)anabaseine;    3-(4-methoxycinnamylidene)anabaseine;    3-(4-hydroxy-2-methoxycinnamylidene)anabaseine;    3-(2,4-dimethoxycinnamylidene)anabaseine;    3-(4-acetoxycinnamylidene)anabaseine;    enantiomers thereof; and    pharmaceutically acceptable salts thereof.