Inhibitors of poly(ADP-ribose) synthetase and use thereof to treat NMDA neurotoxicity

Abstract

Inhibitors of poly(ADP-ribose) synthetase can be used to prevent neurotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors. Poly(ADP-ribose) synthetase inhibitors can be used therapeutically in the treatment of vascular stroke and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

We claim: 
     
       1. A method of treating a disease condition caused by .[.NMDA.]. .Iadd.glutamate .Iaddend.neurotoxicity in a mammal comprising: administering to a mammal which demonstrates symptoms of a disease condition caused by .[.NMDA.]. .Iadd.glutamate .Iaddend.neurotoxicity a therapeutically effective amount of an inhibitor of poly (ADP-ribose) synthetase.   
     
     
       2. The method of claim 1 wherein said inhibitor is administered intravenously, intraperitoneally, intramuscularly, intraventricularly, or orally. 
     
     
       3. The method of claim 2 wherein said inhibitor is benzamide. 
     
     
       4. The method of claim 1 wherein said inhibitor is benzamide. .[.5. The method of claim 1 wherein said inhibitor is a benzamide derivative selected from the group consisting of 3-aminobenzamide and 
     
     
        4-aminobenzamide..].6. The method of claim .[.5.]. .Iadd.1 .Iaddend.wherein said inhibitor is 3-aminobenzamide. .[.7. The method of 
     
     
        claim 5 wherein said inhibitor is 4-aminobenzamide..].8. The method of 
     
     
        claim 1 wherein said inhibitor is 1,5-dihydroxy-isoquinoline. 9. The 
     
     
        method of claim 1 wherein said disease is vascular stroke. 10. The method 
     
     
        of claim 1 wherein said disease is a neurodegenerative disease. 11. A pharmaceutical formulation comprising .Iadd.a therapeutically effective amount of .Iaddend.an inhibitor of poly(ADP-ribose) synthetase .Iadd.containing a single or divided dose having a potency equivalent to about 10 mg/kg of body weight or less of benzamide .Iaddend.in a 
     
     
        pharmaceutically acceptable vehicle. 12. The pharmaceutical formulation of claim 11 wherein said inhibitor is benzamide. .[.13. The pharmaceutical formulation of claim 11 wherein said inhibitor is a benzamide derivative selected from the group consisting of 3-aminobenzamide and 4-amino 
     
     
        benzamide..].14. The pharmaceutical formulation of claim .[.13.]. .Iadd.11 .Iaddend.wherein said inhibitor is 3-aminobenzamide. .[.15. The pharmaceutical formulation of claim 13 wherein said inhibitor is 
     
     
        4-aminobenzamide..].16. The pharmaceutical formulation of claim 11 wherein 
     
     
        said inhibitor is 1,5-dihydroxy-isoquinoline. 17. The pharmaceutical formulation of claim 11 wherein said inhibitor has an IC 50  for inhibiting poly(ADP-ribose) synthetase in vitro of at least .Iadd.as 
     
     
        potent as .Iaddend.22 μM. 18. The pharmaceutical formulation of claim 11 wherein said inhibitor has an IC 50  for inhibiting poly(ADP-ribose) 
     
     
        synthetase in vitro of at least .Iadd.as potent as .Iaddend.33 μM. 19. The pharmaceutical formulation of claim 11 wherein said formulation is a capsule or tablet containing a single or divided dose of said inhibitor, wherein said dose is sufficient to treat .[.NMDA.]. .Iadd.glutamate 
     
     
        .Iaddend.neurotoxicity. 20. The pharmaceutical formulation of claim 11 which is a sterile solution, suspension or emulsion, in a single or divided dose, for administration to a mammal which demonstrates symptoms of a disease condition caused by .[.NMDA.]. .Iadd.glutamate .Iaddend.neurotoxicity. .Iadd.21. The pharmaceutical formulation of claim 11 wherein said formulation is a capsule or tablet containing a single or divided dose of said inhibitor, wherein said dose is sufficient to treat glutamate neurotoxicity mediated through NMDA receptors. .Iaddend..Iadd.22. The pharmaceutical formulation of claim 11 which is a sterile solution, suspension or emulsion, in a single or divided dose, for administration to a mammal which demonstrates symptoms of a disease condition caused by glutamate neurotoxicity mediated through NMDA receptors. .Iaddend..Iadd.23. A method of claim 1 wherein said therapeutically effective amount of an inhibitor of poly (ADP-ribose) synthetase is in the form of a single or divided dose having a potency equivalent to about 10 mg/kg of body weight or less of benzamide. .Iaddend..Iadd.24. A method of treating a disease condition caused by glutamate neurotoxicity in a mammal comprising: administering to a mammal which demonstrates symptoms of a disease condition caused by glutamate neurotoxicity mediated through NMDA receptors a therapeutically effective amount of an inhibitor of poly (ADP-ribose) synthetase. .Iaddend..Iadd.25. The method of claim 24 wherein said inhibitor is administered intravenously, intraperitoneally, intramuscularly, intraventricularly, or orally. .Iaddend..Iadd.26. The method of claim 24 wherein said inhibitor is benzamide. .Iaddend..Iadd.27. The method of claim 25 wherein said inhibitor is benzamide.   
     
     
        .Iaddend..Iadd.8.  The method of claim 24 wherein said inhibitor is 3-aminobenzamide. .Iaddend..Iadd.29. The method of claim 24 wherein said inhibitor is 1,5-dihydroxy-isoquinoline. .Iaddend..Iadd.30. The method of claim 24 wherein said disease is vascular stroke. .Iaddend..Iadd.31. The method of claim 24 wherein said disease is a neurodegenerative disease. .Iaddend..Iadd.32. A method of claim 24 wherein said therapeutically effective amount of an inhibitor of poly (ADP-ribose) synthetase is in the form of a single or divided dose having a potency equivalent to about 10 mg/kg of body weight or less of benzamide. .Iaddend.