6-Acetyl-7,7-dimethyl-5,6,7,8-tetrahydropterin is an activator of nitric oxide synthases
Suckling, Colin J. and Gibson, C.L. and Huggan, Judith K. and Morthala, Raghavendar R. and Clarke, Brendan and Kununthur, Suma and Wadsworth, Roger M. and Daff, Simon and Papale, Davide (2008) 6-Acetyl-7,7-dimethyl-5,6,7,8-tetrahydropterin is an activator of nitric oxide synthases. Bioorganic and Medicinal Chemistry Letters, 18 (5). pp. 1563-1566. ISSN 0960-894X (https://doi.org/10.1016/j.bmcl.2008.01.079)
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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 purified 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.
ORCID iDs
Suckling, Colin J., Gibson, C.L. ORCID: https://orcid.org/0000-0003-4948-1266, Huggan, Judith K., Morthala, Raghavendar R., Clarke, Brendan, Kununthur, Suma, Wadsworth, Roger M., Daff, Simon and Papale, Davide;-
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Item type: Article ID code: 13271 Dates: DateEvent1 March 2008PublishedSubjects: Medicine > Therapeutics. Pharmacology
Medicine > Pharmacy and materia medica
Science > MicrobiologyDepartment: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Faculty of Science > Pure and Applied ChemistryDepositing user: Ms Ann Barker-Myles Date deposited: 19 Oct 2009 09:35 Last modified: 02 Sep 2024 00:39 URI: https://strathprints.strath.ac.uk/id/eprint/13271