Inhibition of neuronal nitric oxide synthase by N-phenacyl imidazoles.
Nitric oxide (NO) mediates a series of physiological processes, including regulation of vascular tone, macrofage-mediated neurotoxicity, platelet aggregation, learning and long-term potentiation, and neuronal transmission. Although NO mediates several physiological functions, overproduction of NO can be detrimental and play multiple roles in several pathological diseases. Accordingly, more potent inhibitors, more selective for neuronal nitric oxide synthase (nNOS) than endothelial NOS (eNOS) or inducible NOS (iNOS), could be useful in the treatment of cerebral ischemia and other neurodegenerative diseases. We recently described the synthesis of a series of imidazole derivatives. Among them N-(4-nitrophenacyl) imidazole (A) and N-(4-nitrophenacyl)-2-methyl-imidazole (B) were considered selective nNOS inhibitors. In the present study the action mechanism of compounds A and B was analyzed. Spectral changes observed in the presence of compound A indicate that this inhibitor exerts its effect without interaction with heme iron. Moreover compounds A and B, inhibit nNOS "noncompetitively" versus arginine, but "competitively" versus BH(4).
Sorrenti
V
V
Department of Biological Chemistry, Medical Chemistry, and Molecular Biology, University of Catania, Italy.
Di Giacomo
C
C
Salerno
L
L
Siracusa
M A
MA
Guerrera
F
F
Vanella
A
A
D000328:Adult; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001894:Borohydrides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006418:Heme / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009578:Nitrobenzenes / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D013379:Substrate Specificity
D001894:Borohydrides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; C427946:N-(4-nitrophenacyl)-2-methylimidazole; C427945:N-(4-nitrophenacyl)imidazole; D009578:Nitrobenzenes; D011993:Recombinant Fusion Proteins; D006418:Heme; D001120:Arginine; C496320:NOS1 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat