Conformationally-restricted arginine analogues as alternative substrates and inhibitors of nitric oxide synthases

Younghee Lee, Michael A. Marletta, Pavel Martasek, Linda J. Roman, Bettie Sue Siler Masters, Richard B. Silverman

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Conformationally restricted arginine analogues (1-5) were synthesized and found to be alternative substrates or inhibitors of the three isozymes of nitric oxide synthase (NOS). A comparison of k(cat)/K(m) values shows that (E)-3,4-didehydro-d,l-arginine (1) is a much better substrate than the corresponding (Z)-isomer (2) and 3-guanidino-d,l-phenylglycine (3), although none is as good a substrate as is arginine; 5-keto-d,l-arginine (4) is not a substrate, but is an inhibitor of the three isozymes. Therefore, it appears that arginine binds to all of the NOS isozymes in an extended (E-like) conformation. None of the compounds exhibits time-dependent inhibition of NOS, but they are competitive reversible inhibitors. Based on the earlier report that N(ω)-propyl-l-arginine is a highly selective nNOS inhibitor (Zhang, H. Q.; Fast, W.; Marletta, M.; Martasek, P.; Silverman, R. B. J. Med. Chem. 1997, 40, 3869), (E)-N(ω)-propyl-3,4-didehydro-d,l-arginine (5) was synthesized, but it was shown to be weakly potent and only a mildly selective inhibitor of NOS. Imposing conformational rigidity on an arginine backbone does not appear to be a favorable approach for selective NOS inhibition. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)1097-1104
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume7
Issue number6
DOIs
StatePublished - Jun 1 1999

Keywords

  • Arginine analogues
  • Conformationally-restricted
  • Enzyme inhibition
  • Nitric oxide synthase

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Conformationally-restricted arginine analogues as alternative substrates and inhibitors of nitric oxide synthases'. Together they form a unique fingerprint.

  • Cite this