Method of inhibiting neurotrophin-receptor binding

Abstract

The present invention relates to compositions which inhibit the binding of nerve growth factor to the p75 NTR common neurotrophin receptor and methods of use thereof. In one embodiment, the compound which inhibits binding of nerve growth factor to p75 NTR comprises, particularly when bound to nerve growth factor, at least two of the following: (1) a first electronegative atom or functional group positioned to interact with Lys 34 of nerve growth factor; (2) a second electronegative atom or functional group positioned to interact with Lys 95 of nerve growth factor; (3) a third electronegative atom or functional group positioned to interact with Lys 88 of nerve growth factor; (4) a fourth electronegative atom or functional group positioned to interact with Lys 32 of nerve growth factor; and (5) a hydrophobic moiety which interacts with the hydrophobic region formed by Ile 31 , Phe 101 and Phe 86 of nerve growth factor.

1 . A method of inhibiting the binding of nerve growth factor to the p 75   NTR  receptor, comprising contacting the cells expressing the p 75   NTR  receptor with an effective inhibiting amount of a compound of Formula 1,  
     
       
         
         
             
             
         
       
     
     wherein 
 D 1 , D 2 , E 1 , E 2  and G are each, independently, an sp 2 -hybridized carbon or nitrogen atom;  
 one of X 1  and X 2  is a hydrogen atom or absent, while the other is an electronegative atom or an electronegative functional group;  
 R and R 2  are each, independently, an electronegative atom or an electronegative functional group;  
 Y is N, O, S, C—L or N—L, where L is H, alkyl or an electronegative atom or functional group;  
 Z and Z 1  are each, independently, O, S, CH, C(O), N, NH, N-alkyl, N-cycloalkyl or N—P, where P is a carbohydrate moiety;  
 T 1  and T 2  are each, independently, an sp 2 - or sp 3 -hybribized carbon or nitrogen atom;  
 a, b and c are each 0 or 1, provided that at least one of b and c is 1; and  
 R 1  is a monocyclic or polycyclic aryl or heteroaryl, monosachharide or oligosaccharide, alkyl, cycloalkyl, arylalkyl, alkylamino or alkoxy group which is substituted with at least one substituent selected from the group consisting of electronegative atoms and electronegative functional groups.  
 
   
   
       2 .- 101 . (canceled)