Treatment of neurodegenerative diseases, causation of memory enhancement, and assay for screening compounds for such

Abstract

Methods for enhancing memory and/or learning and prevent neurodegeneration by administration of certain heterocyclic and aromatic compounds are described. The methods are particularly useful for treating patients suffering from a neurodegenerative disease such as (without limitation) Alzheimer's, Parkinsons's, Lou Gehrig's (ALS) disease or memory or learning impairment. A neuronal human cell-based assay that assess NF-kB gene up-regulation using a luciferase reporter is also provided that screens for compounds useful in methods for enhancing memory or learning.

What is claimed is: 
     
         1 . A method for enhancing memory comprising administering to a patient in need thereof a memory enhancing amount of at least one compound selected from the group consisting of compounds represented by the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein, 
         in Structure 1, 
         Z represents O, NH, N—R 3 , S, CH, or CR 3 ; and 
         each R 1 , R 2  and R 3  is individually selected from the group consisting of substituted or unsubstituted alkyl, aryl, aralkyl and heteroaryl; 
         in Structure 1a, 
         Z represents N, CH, or CR 3  a; and 
         each R 1 , R 2  and R 3  is individually selected from the group consisting of substituted or unsubstituted alkyl, aryl, aralkyl and heteroaryl; 
         in Structure 2, 
         Y is O or S; 
         R 1  is H, acyl, substituted or unsubstituted alkyl, aryl, aralkyl and heteroaryl; 
         each R 2  and R 4  is individually selected from the group consisting of substituted or unsubstituted alkyl, aryl, aralkyl and heteroaryl; and 
         R 3  is selected from the group consisting of H or substituted or unsubstituted alkyl, aryl, aralkyl and heteroaryl; 
         in Structure 3, 
         X represents OR 6  or NR 6 R 7 ; 
         each R 1  and R 2  is individually selected from the group consisting of single or multiple substitutions of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, and amino or substituted amino; 
         each R 3 , R 4  and R 6  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl and heteroaryl; and 
         each R 5  and R 7  is individually selected from the group consisting of H, acyl, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; 
         in Structure 4, 
         each W, X, Y, Z is N or CR 6 ; 
         each R 1 , R 2 , R 4 , R 5  and R 6  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; and 
         R 3  is H, acyl, substituted or unsubstituted alkyl, aryl, aralkyl and heteroaryl; 
         in Structure 5, 
         each R 1 , R 2 , R 3  and R 4  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; 
         in Structure 5a, 
         X represents N or CR 2 ; 
         Y represents S or CR 5 R 6 ; and 
         each R 1 , R 2 , R 3 , R 4 , R 5  and R 6  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; 
         in Structure 6, 
         X represents R 2  or NR 3 R 4 ; 
         Y represents O, S or NR 5 ; 
         R 1  is selected from the group consisting of single or multiple substitutions of H or substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, and amino or substituted amino; 
         each R 2 , R 3 , and R 5  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; and 
         R 4  is H, acyl, substituted or unsubstituted alkyl, aryl, aralkyl and heteroaryl; 
         in Structure 7, 
         X represents O—R 4  or NR 4 R 5 ; 
         each R 1 , R 2 , R 3 , and R 4  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; and 
         R 5  is H, acyl, substituted or unsubstituted alkyl, aryl, aralkyl and heteroaryl; 
         in Structure 8, 
         X represents O or S; 
         Y represents N or CR 3 ; 
         Z represents NR 4 R 5  or CR 4 R 5 R 6 ; 
         each R 3 , R 4 , and R 6  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; and 
         n is o, 1, 2, 3, or 4; 
         in Structure 9, 
         X represents O, S or NR 4 ; 
         R 1  is selected from the group consisting of single or multiple substitutions of H or substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl or acyl, halogen, hydroxy, alkoxy, amino or substituted amino; and 
         each R 2 , R 3 , and R 4  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; 
         in Structure 10, 
         R 1 , is selected from the group consisting of single or multiple substitutions of H or substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, and amino or substituted amino; 
         R 2  is selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; 
         R 3  is H, acyl, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; 
         m is 0, 1, 2, or 3; and 
         n is 1, 2, or 3; 
         in Structure 10a, 
         R 1  is selected from the group consisting of single or multiple substitutions of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, and amino or substituted amino; 
         R 4  is selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; 
         R 3  is H, acyl, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; and m is 0, 1, 2, or 3; 
         in Structure 11, 
         R 1  is selected from the group consisting of single or multiple substitutions of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, and amino or substituted amino; 
         R 2  is selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; and 
         R 3  is H, acyl, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; 
         in Structure 12, 
         R 1  is selected from the group consisting of single or multiple substitutions of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, and amino or substituted amino; 
         R 2  is selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; and 
         R 3  is H, acyl, substituted or unsubstituted alkyl, aryl, aralkyl, and heteroaryl; 
         in Structure 13, 
         each R 1  and R 2  is individually selected from the group consisting of single or multiple substitutions of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, and amino or substituted amino; 
         in Structure 14, 
         R 1  is selected from the group consisting of single or multiple substitutions of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, and amino or substituted amino; and 
         each R 2  and R 3  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, amino or substituted amino, alkylthio, cyano, and azido; 
         in Structure 15, 
         R 1  is selected from the group consisting of single or multiple substitutions of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, amino or substituted amino, cyano, and alkylthio; and 
         each R 2  and R 3  is individually selected from the group consisting of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, amino or substituted amino, cyano, and alkylthio; and 
         in Structure 16, 
         each R 1  and R 2  is individually selected from the group consisting of single or multiple substitutions of H, substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl, acyl, halogen, hydroxy, alkoxy, amino or substituted amino, cyano, azido, and alkylthio.