Inhibition of nitric oxide synthase by 1-(2-trifluoromethylphenyl) imidazole (TRIM) in vitro: antinociceptive and cardiovascular effects

摘要

1 The ability of a range of substituted imidazole compounds to inhibit mouse cerebellar neuronal nitric oxide synthase (nNOS), bovine aortic endothelial NOS (eNOS) and inducible NOS (iNOS) from lungs of endotoxin-pretreated rats was investigated. In each case the substrate (L-arginine) concentration employed was 120 nM. 2 1-(2-Trifluoromethylphenyl) imidazole (TRIM) was a relatively potent inhibitor of nNOS and iNOS (IC_(50)s of 28.2 μM and 27.0 μM respectively) but was a relatively weak inhibitor of eNOS (IC_(50), 1057.5 μM). The parent compound, imidazole, was a weak inhibitor of all three NOS isoforms (IC_(50)s: nNOS, 290.6 μM; eNOS, 101.3 μM; iNOS, 616.0 μM). Substitution of imidazole with a phenyl group to yield 1-phenylimidazole (PI) resulted in an isoform non-selective increase in inhibitory potency (IC_(50)s: nNOS, 72.1 μM; eNOS, 86.9 μM; iNOS, 53.9 μM). Further substitution of the attached phenyl group resulted in an increase in nNOS and a decrease in eNOS inhibitory potency as in TRIM, 1-chlorophenylimidazole (CPI; IC_(50)s: nNOS, 43.4 μM; eNOS, 392.3 μM; iNOS, 786.5 μM) and 1-(2,3,5,6-tetrafluorophenyl) imidazole (TETRA-FPI; IC_(50)s: nNOS, 56.3 μM; eNOS, 559.6 μM; iNOS, 202.4 μM).