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

Academic Article
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Overview

authors

  • Lee, Y.
  • Marletta, Michael
  • Martasek, P.
  • Roman, L. J.
  • Masters, B. S. S.
  • Silverman, R. B.

publication date

  • June 1999

journal

  • Bioorganic & Medicinal Chemistry  Journal

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)/Km 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(omega)-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(omega)-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.

subject areas

  • Animals
  • Arginine
  • Enzyme Inhibitors
  • Isoenzymes
  • Mice
  • Molecular Structure
  • Nitric Oxide Synthase
  • Substrate Specificity
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Research

keywords

  • arginine analogues
  • conformationally-restricted
  • enzyme inhibition
  • nitric oxide synthase
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Identity

International Standard Serial Number (ISSN)

  • 0968-0896

Digital Object Identifier (DOI)

  • 10.1016/s0968-0896(99)00029-2

PubMed ID

  • 10428379
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Additional Document Info

start page

  • 1097

end page

  • 1104

volume

  • 7

issue

  • 6

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