NG-allyl- and NG-cyclopropyl-L-arginine: two novel inhibitors of macrophage nitric oxide synthase.
NG-Methyl-L-arginine has recently been shown to inactivate the inducible murine macrophage nitric oxide (.NO) synthase (Olken, N. M.; Rusche, K. M.; Richards, M. K.; Marletta, M. A. Biochem. Biophys. Res. Commun. 1991, 177, 828-833). NG-Allyl-L-arginine and NG-cyclopropyl-L-arginine were synthesized as potential mechanism-based enzyme inhibitors to exploit the chemistry presumed to occur at the active site. NG-Cyclopropyl-L-arginine was found to be a potent reversible inhibitor with a Ki = 7.7 microM. NG-Allyl-L-arginine was found to be both a potent reversible (Ki = 2.1 microM) and irreversible inhibitor of the enzyme. This irreversible inhibition demonstrated pseudo-first-order inactivation kinetics with kinact = 0.026 min-1 and KI = 3.4 microM. Stereospecific protection of the inactivation was afforded by L-arginine, and saturability of the inactivation rate was observed. Our studies indicate that both reversible and irreversible inhibition of the inducible .NO synthase can be achieved with relatively simple modifications of the substrate L-arginine.
Olken
N M
NM
Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
Marletta
M A
MA
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D019001:Nitric Oxide Synthase
D004791:Enzyme Inhibitors; C073754:omega-N-cyclopropylarginine; C073753:omega-N-allylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases