N(ω)-Propargyl-L-arginine and N(ω)-hydroxy-N(ω)-propargyl-L-arginine are inhibitors, but not activators, of neuronal and macrophage nitric oxide synthases

Walter Fast, Marc E. Levsky, Michael A. Marletta, Richard B. Silverman

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

N(ω)-Propargyl-L-arginine (7) was synthesized as a potential mechanism-based inactivator of neuronal nitric oxide synthase (nNOS) and macrophage nitric oxide synthase (iNOS). Compound 7 is a potent reversible competitive inhibitor for both isoforms, having K(i) values of 430 ± 50 nM and 620 ± 30 nM for nNOS and iNOS, respectively. These values 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 inhibition with either. It also only undergoes oxidation very slowly. N(ω)-Hydroxy-N(ω)-propargyl-L-arginine also was synthesized to determine if the initial proposed enzyme-catalyzed hydroxylation of N(ω)-propargyl-L-arginine was problematic. This compound also is a potent reversible inhibitor of both nNOS and iNOS, but is not a time-dependent inactivator and is oxidized only very slowly. These results are in sharp contrast with the corresponding olefins, N(ω)-allyl-L-arginine and N(ω)-allyl-N(ω)-hydroxy-L-arginine recently reported to be potent time-dependent, irreversible inhibitors of nNOS (Zhang, H.Q.; Dixon, R.P.; Marletta, M.A.; Silverman, R.B., J. Am. Chem. Sec. 1997, 119, in press); N(ω)-allyl-L-arginine also was reported to be an inactivator of iNOS (Olken, N.M.; Marletta, M.A. J. Med. Chem. 1992, 35, 1137). This suggests that the active site of both isoforms of NOS can accommodate a variety of structures, but binding must have the appropriate juxtaposition for hydroxylation; otherwise, no oxidation occurs.

Original languageEnglish (US)
Pages (from-to)1601-1608
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume5
Issue number8
DOIs
StatePublished - Aug 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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