Inhibition of Neuronal Nitric Oxide Synthase by N-Phenacyl Imidazoles

Nitric oxide (NO) mediates a series of physiologicalprocesses, including regulation of vascular tone,macrofage-mediated neurotoxicity, platelet aggregation,learning and long-term potentiation, andneuronal transmission. Although NO mediates severalphysiological functions, overproduction of NOcan be detrimental and play multiple roles in severalpathological diseases. Accordingly, more potentinhibitors, more selective for neuronal nitricoxide synthase (nNOS) than endothelial NOS(eNOS) or inducible NOS (iNOS), could be useful inthe treatment of cerebral ischemia and other neurodegenerativediseases. We recently described thesynthesis of a series of imidazole derivatives.Among them N-(4-nitrophenacyl) imidazole (A) andN-(4-nitrophenacyl)-2-methyl-imidazole (B) wereconsidered selective nNOS inhibitors. In thepresent study the action mechanism of compoundsA and B was analyzed. Spectral changes observed inthe presence of compound A indicate that this inhibitorexerts its effect without interaction withheme iron. Moreover compounds A and B, inhibitnNOS ªnoncompetitivelyº versus arginine, butªcompetitivelyº versus BH4.