6-acetyl-7,7-dimethyl-5,6,7,8-tetrahydropterin is an activator of nitric oxide synthases

Colin J. Suckling, Colin L. Gibson, Judith K. Huggan, Raghavendar R. Morthala, Brendan Clarke, Suma Kununthur, Roger M. Wadsworth, Simon Daff, Davide Papale

Research output: Contribution to journalArticlepeer-review

Abstract

6-Acetyl-7,7-dimethyl-7,8-dihydropterin 3 has been shown to be able to substitute for the natural cofactor of nitric oxide synthases, tetrahydrobiopterin 1, in cells and tissues that contain active nitric oxide synthases (NOSs). In both macrophages, which produce iNOS, and endothelial cells, which produce eNOS, in which tetrahydrobiopterin biosynthesis has been blocked by inhibition of GTP cyclohydrolase 1, dihydropterin 3 restored production of nitric oxide by these cells. In tissues, 3 caused relaxation in preconstricted rat aortic rings, again in which tetrahydrobiopterin biosynthesis had been inhibited, an effect that was blocked by the NOS inhibitor, L-NAME. However, dihydropterin 3 was not itself an active cofactor in purifed NOS ( nNOS) preparations free of tetrahydrobiopterin suggesting that intracellular reduction to 6-acetyl-7,7-dimethyl-5,6,7,8-tetrahydropterin 4 is required for activity. Compound 4 was prepared by reduction of the corresponding 7,8-dihydropterin with sodium cyanoborohydride and has been shown to be a competent cofactor for nitric oxide production by nNOS. Together, the results show that the 7,7-dimethyl-7,8-dihydropterin is a novel structural framework for effective tetrahydrobiopterin analogues. (c) 2008 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)1563-1566
Number of pages4
JournalBioorganic & Medicinal Chemistry Letters
Volume18
Issue number5
DOIs
Publication statusPublished - 1 Mar 2008

Keywords

  • pteridines
  • nitric oxide synthases
  • tetrahydrobiopterin replacement
  • 7,7-dialkylpteridines
  • VITAMIN BIOSYNTHESIS
  • ELECTRON-TRANSFER
  • INHIBITORS
  • TETRAHYDROBIOPTERIN
  • DERIVATIVES
  • COFACTOR

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