NG-Allyl- and NG-Cyclopropyl-L-arginine: Two Novel Inhibitors of Macrophage Nitric Oxide Synthase

Article abstract of DOI:10.1021/jm00084a020

N^G-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).N^G-Allyl-L-arginine and N^G-cyclopropyl-L-arginine were synthesized as potential mechanism-based enzyme inhibitors to exploit the chemistry presumed to occur at the active site.N^G-Cyclopropyl-L-arginine was found to be a potent reversible inhibitor with a K_i = 7.7 μM.N^G-Allyl-L-arginine was found to be both a potent reversible (K_i = 2.1 μM) and irreversible inhibitor of the enzyme.The irreversible inhibition demonstrated pseudo-first-order inactivation kinetics with k_inact = 0.026 min^-1 and K_i = 3.4 μM.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.