N-OMEGA-PROPARGYL-L-ARGININE AND N-OMEGA-HYDROXY-N-OMEGA-PROPARGYL-L-ARGININE ARE INHIBITORS, BUT NOT INACTIVATORS, OF NEURONAL AND MACROPHAGE NITRIC-OXIDE SYNTHASES

N-omega-Propargyl-L-arginine (7) was synthesized as a potential mechan ism-based inactivator of neuronal nitric oxide synthase (nNOS) and mac rophage nitric oxide synthase (iNOS). Compound 7 is a potent reversibl e competitive inhibitor for both isoforms, having K-i values of 430 +/ - 50 nM and 620 +/- 30 nM for nNOS and iNOS, respectively. These value s are 12 and 32 times lower than the K-m for L-arginine with nNOS and iNOS, respectively; however, 7 does not exhibit time-dependent inhibit ion with either. It also only undergoes oxidation very slowly. N-omega -Hydroxy-N-omega-propargyl-L-arginine also was synthesized to determin e if the initial proposed enzyme-catalyzed hydroxylation of N-omega-pr opargyl-L-arginine was problematic. This compound also is a potent rev ersible inhibitor of both nNOS and iNOS, but is not a time-dependent i nactivator and is oxidized only very slowly. These results are in shar p contrast with the corresponding olefins, N-omega-allyl-L-arginine an d N-omega-allyl-N-omega-hydroxy-L-arginine recently reported to be pot ent time-dependent, irreversible inhibitors of nNOS (Zhang, H. Q.; Dix on, R. P.; Marletta, M. A.; Silverman, R. B., J. Am. Chem. Sec. 1997, 119, in press); N-omega-allyl-L-arginine also was reported to be an in activator of iNOS (Olken, N. M.; Marletta, M. A. J. Med. Chem. 1992, 3 5, 1137). This suggests that the active site of bath isoforms of NOS c an accommodate a variety of structures, but binding must have the appr opriate juxtaposition for hydroxylation; otherwise, no oxidation occur s. (C) 1997 Elsevier Science Ltd.