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 - 42 . (canceled) 
     
     
         43 . A compound having Formula 4: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein 
 X is NO 2 ; and 
 R 1  is CH 2 (CH 2 ) 3 COOH. 
 
     
     
         44 . The compound of  claim 43 , wherein the compound having Formula 4 is N-(4-carboxybutyl)-3-nitro-1,8-naphthalimide or N-(4-carboxybutyl)-4-nitro-1,8-naphthalimide. 
     
     
         45 . The compound N-(2-carboxyethyl)-4-nitro-1,8-naphthalimide. 
     
     
         46 . The compound N-(3-carboxypropyl)-3-nitro-1,8-naphthalimide. 
     
     
         47 . A method of treating Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke or pain in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of a compound having Formula 4: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein 
 X is 3-NO 2  or 4-NO 2 ; and 
 R 1  is CH 2 (CH 2 ) 2 COOH, or CH 2 (CH 2 ) 3 COOH. 
 
     
     
         48 . The method of  claim 47 , wherein X is 3-NO 2  or 4-NO 2 . 
     
     
         49 . The method of  claim 47 , wherein the compound having Formula 4 is N-(3-carboxypropyl)-3-nitro-1,8-naphthalimide; N-(4-carboxybutyl)-3-nitro-1,8-naphthalimide; N-(3-carboxypropyl)-4-nitro-1,8-naphthalimide; or N-(4-carboxybutyl)-4-nitro-1,8-naphthalimide. 
     
     
         50 . The method of  claim 47 , wherein the compound having Formula 4 is N-(3-carboxypropyl)-3-nitro-1,8-naphthalimide. 
     
     
         51 . A method of treating Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke or pain in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of N-(2-carboxyethyl)-4-nitro-1,8-naphthalimide. 
     
     
         52 . A method of inhibiting the binding of nerve growth factor to the p75 NTR  receptor, comprising contacting cells expressing the p75 NTR  receptor with an effective inhibiting amount of a compound having Formula 4: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein 
 X is NO 2 ; and 
 R 1  is CH 2 (CH 2 ) 2 COOH, or CH 2 (CH 2 ) 3 COOH. 
 
     
     
         53 . The method of  claim 52 , wherein X is 3-NO 2  or 4-NO 2 . 
     
     
         54 . The method of  claim 52 , wherein the compound having Formula 4 is N-(3-carboxypropyl)-3-nitro-1,8-naphthalimide; N-(4-carboxybutyl)-3-nitro-1,8-naphthalimide; N-(3-carboxypropyl)-4-nitro-1,8-naphthalimide; or N-(4-carboxybutyl)-4-nitro-1,8-naphthalimide. 
     
     
         55 . The method of  claim 52 , wherein the compound having Formula 4 is N-(3-carboxypropyl)-3-nitro-1,8-naphthalimide. 
     
     
         56 . A method of inhibiting the binding of nerve growth factor to the p75 NTR  receptor, comprising contacting cells expressing the p75 NTR  receptor with an effective inhibiting amount N-(2-carboxyethyl)-4-nitro-1,8-naphthalimide.
 Y, Y 1 , Y 2 , and Y 3  are each, independently, 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 -hybridized carbon or nitrogen atom;   d, h and c are each 0 or 1; and   R 1  is a monocyclic or polycyclic aryl or heteroaryl group
 group which is substituted with at least one substituent selected from the group consisting of hydroxyl and sulfonamide or an alkyl or alkylamino group substituted with a carboxyl or carbonate group; and 
   at least one pharmaceutically acceptable carrier or excipient.