Selective neuronal nitric oxide synthase inhibitors

Abstract

Peptidomimetic compositions for selective inhibition of neuronal nitric oxide synthase.

1 . An N-nitroarginine-containing dipeptide composition having the structural formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of hydrogen, alkyl, and a prolinyl moiety; and R 2  is selected from the group consisting of amino, alkyl, aminoalkyl, an aminoprolinamide moiety, and a diaminocyclopentanecarboxamide moiety.  
     
     
         2 . The composition of  claim 1  wherein said composition is a hydrate.  
     
     
         3 . The composition of  claim 1  wherein said composition is a mixture of stereoisomers.  
     
     
         4 . The composition of  claim 3  wherein said composition is an acid salt.  
     
     
         5 . The composition of  claim 1  wherein R 1  is a 4-aminoprolinyl moiety.  
     
     
         6 . A dipeptide composition comprising an N-nitroarginine (Arg NO     2   ) residue coupled with an amide bond at a terminus of said nitroarginine residue to an amino-substituted proline (Pro NH     2   ) residue, said composition having a formula selected from the group consisting of: 
 Arg NO     2   -Pro NH     2   , wherein said substituted proline residue is coupled to the N-terminus of said nitroarginine residue; and    Pro NH     2   -Arg NO     2   -NH 2 , wherein said substituted proline residue is coupled to the C-terminus of said nitroarginine residue.    
     
     
         7 . The composition of  claim 6  wherein said formula is Arg NO     2   -Pro NH     2   , and said nitroarginine residue has a stereochemical configuration selected from the group of consisting of D- and L-isomers.  
     
     
         8 . The composition of  claim 7  wherein said nitroarginine residue has an L-configuration and said proline residue has a 4-amino substituent and a trans diastereomeric configuration.  
     
     
         9 . The composition of  claim 8  having a formula selected from the group  
     
     
         10 . A method of using a proline residue to affect nitric oxide synthase inhibition, said method comprising: 
 providing a dipeptide composition having an N-nitroarginine residue coupled with an amide bond at a terminus of said nitroarginine residue to an amino-substituted proline residue; and    interacting said dipeptide composition with an isoform of nitric oxide synthase, said composition in an amount sufficient to inhibit nitric oxide synthase activity on an available arginine substrate.    
     
     
         11 . The method of  claim 10  wherein said dipeptide composition is selected from the group of compositions of  claim 6 .  
     
     
         12 . The method of  claim 11  wherein said substituted proline residue has a 4-amino substituent, is coupled to the C-terminus of said nitroarginine residue, and has a trans-diastereomeric configuration.  
     
     
         13 . The method of  claim 12  wherein interaction of said dipeptide composition selectively inhibits the neuronal isoform of nitric oxide synthase, over the inducible and endothelial isoforms of nitric oxide synthase.  
     
     
         14 . A peptidomimetic N-nitroguanidinyl composition having the structural formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is XNHR 2 , and X is a moiety selected from the group consisting of CH 2  and C(O); and R 2  is selected from the group consisting of CH 2 (CH 2 ) n NH 2 , where n=1-3;  
       
         
           
           
               
               
           
         
       
       where n=0-2; and  
       
         
           
           
               
               
           
         
       
       where m=0-2 and n=0-2.  
     
     
         15 . The composition of  claim 14  wherein X is a CH 2  moiety.  
     
     
         16 . The composition of  claim 15  wherein R 2  is CH 2 (CH 2 ), n NH 2  and n=1-3.  
     
     
         17 . The composition of  claim 15  wherein R 2  is  
       
         
           
           
               
               
           
         
       
       where n=0-2.  
     
     
         18 . The composition of  claim 15  wherein R 2  is  
       
         
           
           
               
               
           
         
       
       where m=0-2 and n=0-2.  
     
     
         19 . A method of using amide bond reduction to affect nitric oxide synthase inhibition, said method comprising: 
 providing an N-nitroarginine analog composition with a reduced amide bond, said composition having the structural formula                          wherein R 1  is XNHR 2 , and X is a moiety selected from the group consisting of CH 2  and C(O); and R 2  is selected from the group consisting of CH 2 (CH 2 ) n NH 2 , where n=1-3;                          where n=0-2; and                          where m=0-2 and n=0-2; and    interacting said reduced amide analog composition with an isoform of nitric acid synthase, said composition in an amount sufficient to inhibit nitric oxide formation.    
     
     
         20 . The method of  claim 19  wherein R 2  is CH 2 (CH 2 ) n NH 2  and n=1-3.  
     
     
         21 . The method of  claim 19  wherein R 2  is  
       
         
           
           
               
               
           
         
       
       where n=0-2.  
     
     
         22 . The method of  claim 19  wherein R 2  is  
       
         
           
           
               
               
           
         
       
       where m=0-2 and n=0-2.  
     
     
         23 . The method of  claim 19  wherein interaction of said composition selectively inhibits the neuronal isoform of nitric oxide synthase over the inducible and endothelial isoforms of nitric oxide synthase.