title: 6-Acetyl-7,7-dimethyl-5,6,7,8-tetrahydropterin is an activator of nitric oxide synthases.
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 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.
authors.affiliation: WestCHEM, Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL Scotland, UK. c.j.suckling@strath.ac.uk
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.forename: Colin L
authors.initials: CL
authors.lastname: Gibson
authors.forename: Judith K
authors.initials: JK
authors.lastname: Huggan
authors.forename: Raghavendar R
authors.initials: RR
authors.lastname: Morthala
authors.forename: Brendan
authors.initials: B
authors.lastname: Clarke
authors.forename: Suma
authors.initials: S
authors.lastname: Kununthur
authors.forename: Roger M
authors.initials: RM
authors.lastname: Wadsworth
authors.forename: Simon
authors.initials: S
authors.lastname: Daff
authors.forename: Davide
authors.initials: D
authors.lastname: Papale
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000737:chemistry* / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011622:Pterins / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats
chemical_list: C528891:6-acetyl-7,7-dimethyl-5,6,7,8-tetrahydropterin; D020536:Enzyme Activators; D011622:Pterins; D019001:Nitric Oxide Synthase