Methods and assays useful in the treatment of alcohol dependence or alcohol abuse

Abstract

A method for the treatment of alcohol abuse using daidzin and compounds analogous to daidzin is disclosed. Also disclosed is a method for screening compounds having antidipsotropic activity.

1 . A method for inhibiting ALDH-2 in a human comprising contacting ALDH-2 with a compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein: 
 R is substituted or unsubstituted and is a  
 sugar moiety;  
 peptide;  
 polyether;  
 straight chain alkyl having 1-11 carbon atoms, or branched chain alkyl having 1-30 carbon atoms, where the branched chain alkyl comprises a straight chain alkyl portion having 1-11 carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms;  
 hydroxyalkyl where the alkyl portion is straight chain alkyl having 2-11 carbon atoms, or branched chain alkyl having 2-30 carbon atoms, where the branched chain alkyl comprises a straight chain alkyl portion having 2-11 carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms;  
 aminoalkyl where the alkyl portion is straight chain alkyl having 2-11 carbon atoms, or branched chain alkyl having 2-30 carbon atoms, where the branched chain alkyl comprises a straight chain alkyl portion having 2-11 carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms;  
 carboxyalkyl where the alkyl portion is straight chain alkyl having 2-11 carbon atoms, or branched chain alkyl having 2-30 carbon atoms, where the branched chain alkyl comprises a straight chain alkyl portion having 2-11 carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms; or  
                     
 or  
 where X is straight chain alkylene having 2-11 carbon atoms, or branched chain alkylene having 2-30 carbon atoms, where the branched chain alkylene comprise a straight chain alkylene portion having 2-11 carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms; and  
 R′ is straight or branched alkyl having 1-6 carbon atoms, in an amount effective to increase concentration of 5-hydroxyindole-3-acetic acid or 3,4-dihydroxyphenylacetic acid.  
 
   
   
       2 . The method of  claim 1  wherein the sugar moiety is glucosyl, L or D aldo or keto-tetrose, pentose, heptose, an amino, alcohol or acid derivative of tetrose, pentose, hexose or heptose, a deoxyanalog of tetrose, pentose, hexose or heptose.  
   
   
       3 . A method for therapeutically treating alcohol consumption in a human comprising administering a compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein: 
 R is substituted  
 or unsubstituted and is a  
 sugar moiety;  
 peptide;  
 polyether;  
 straight chain alkyl having 1-11 carbon atoms, or branched chain alkyl having 1-30 carbon atoms, where the branched chain alkyl comprises a straight chain alkyl portion having 1-1I carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms;  
 hydroxyalkyl where the alkyl portion is straight chain alkyl having 2-11 carbon atoms, or branched chain alkyl having 2-30 carbon atoms, where the branched chain alkyl comprises a straight chain alkyl portion having 2-11 carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms;  
 aminoalkyl where the alkyl portion is straight chain alkyl having 2-11 carbon atoms, or branched chain alkyl having 2-30 carbon atoms, where the branched chain alkyl comprises a straight chain alkyl portion having 2-11 carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms;  
 carboxyalkyl where the alkyl portion is straight chain alkyl having 2-11 carbon atoms, or branched chain alkyl having 2-30 carbon atoms, where the branched chain alkyl comprises a straight chain alkyl portion having 2-11 carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms; or  
                     
 where X is straight chain alkylene having 2-11 carbon atoms, or branched chain alkylene having 2-30 carbon atoms, where the branched chain alkylene comprise a straight chain alkylene portion having 2-11 carbon atoms substituted with straight or branched chain lower alkyl groups having 1-6 carbon atoms; and  
 R′ is straight or branched alkyl having 1-6 carbon atoms,  
 in an amount effective to increase concentration of an aldehyde formed during catabolism of a neurotransmitter.  
 
   
   
       4 . The method of  claim 3  wherein the sugar moiety is glucosyl, L or D aldo or keto-tetrose, pentose, heptose, an amino, alcohol or acid derivative of tetrose, pentose, hexose or heptose, a deoxyanalog of tetrose, pentose, hexose or heptose.  
   
   
       5 . The method of  claim 3  wherein the neurotransmitter is serotonin or dopamine.  
   
   
       6 . The method of  claim 3  wherein the aldehyde is 5-hydroxyindole-3-acetaldehyde or 3,4-dihydroxyphenyl-3-acetaldehyde.  
   
   
       7 . A method for identifying compounds effective in reducing alcohol consumption comprising selecting a test compound, 
 establishing a neurotransmitter enzyme system,    allowing catabolism of a neurotransmitter into aldehyde,    allowing catabolism of aldehyde into carboxylic acid,    measuring a first concentration of aldehyde,    contacting the candidate compound with the neurotransmitter enzyme system,    measuring a second concentration of aldehyde,    comparing the first concentration to the second concentration.    
   
   
       8 . The method of  claim 7  wherein the neurotransmitter is serotonin or dopamine.  
   
   
       9 . The method of  claim 7  wherein the aldehyde is 5-hydroxyindole-3-acetic acid or 3,4-dihydroxyphenylacetic acid.  
   
   
       10 . A method for identifying compounds effective in reducing alcohol consumption comprising selecting a test compound, 
 establishing a neurotransmitter enzyme system,    allowing catabolism of a neurotransmitter into aldehyde,    allowing catabolism of aldehyde into carboxylic acid,    contacting the candidate compound with the neurotransmitter enzyme system,    measuring a concentration of aldehyde, and    comparing the concentration of aldehyde with concentrations of aldehyde produced by compounds having known antidipsotropic activity.    
   
   
       11 . The method of  claim 10  wherein the neurotransmitter is serotonin or dopamine.  
   
   
       12 . The method of  claim 10  wherein the aldehyde is 5-hydroxyindole-3-acetic acid or 3,4-dihydroxyphenylacetic acid.