Acrylamide analog as a novel nitric oxide-independent soluble guanylyl cyclase activator.

摘要: Abstract Soluble guanylyl cyclase (sGC) is a target enzyme for endogenous nitric oxide (NO), and it converts GTP to cyclic GMP (guanosine 3’,5’-cyclic monophosphate) as part of cascade that results in physiological processes such smooth muscle relaxation, neurotransmission, inhibition platelet aggregation. Here we examine representative the novel class sCG activators, A-778935 ((±)- cis -3-[2-(2,2-dimethyl-propylsulfanyl)-pyridin-3-yl]- N -(3-hydroxycyclohexyl)-acrylamide). activated sGC synergistically with sodium nitroprusside (SNP) over wide range concentration, inducing up 420-fold activation. A specific inhibitor sGC, ODQ (1 H -[1,2,4]-oxadiazolo[4,3- α ]quinoxalin-1-one), did not block basal activity, but competitively inhibited activation by A-778935. A-778935, or without SNP, activate heme-deficient indicating fully heme-dependent. increased intracellular cGMP level dose-dependently cells. In presence 1 µ M lower concentration than alone, reached same at 100 relaxed cavernosum tissue strips dose-dependent manner; more potently, shifting dose-response curve left. This activator may have potential efficacy treatment variety disorders associated reduced NO signaling.