Inhibition of neuronal nitric oxide synthase by N-phenacyl imidazoles

Nitric oxide (NO) mediates a series of physiological processes, including r egulation of vascular tone, macrofage-mediated neurotoxicity, platelet aggr egation, learning and long-term potentiation, and neuronal transmission. Al though NO mediates several physiological functions, overproduction of NO ca n be detrimental and play multiple roles in several pathological diseases. Accordingly, more potent inhibitors, more selective for neuronal nitric oxi de synthase (nNOS) than endothelial NOS (eNOS) or inducible NOS (iNOS), cou ld be useful in the treatment of cerebral ischemia and other neurodegenerat ive diseases. We recently described the synthesis of a series of imidazole derivatives. Among them N-(4-nitrophenacyl) imidazole (A) and N-(4-nitrophe nacyl)-2-methyl-imidazole (B) were considered selective nNOS inhibitors. In the present study the action mechanism of compounds A and E was analyzed. Spectral changes observed in the presence of compound A indicate that this inhibitor exerts its effect without interaction with heme iron. Moreover co mpounds A and B, inhibit nNOS "noncompetitively" versus arginine, but "comp etitively" versus BH4. (C) 2001 Academic Press.