title: A-350619: a novel activator of soluble guanylyl cyclase.
abstract: Nitric oxide (NO) is a key mediator in many physiological processes and one of the major receptors through which NO exerts its effects is soluble guanylyl cyclase. Guanylyl cyclase converts GTP to cyclic GMP as part of the cascade that results in physiological processes such as smooth muscle relaxation, neurotransmission, inhibition of platelet aggregation and immune response. The properties of A-350619, a novel soluble guanylyl cyclase activator, were examined to determine the modulatory effect on the catalytic properties of soluble guanylyl cyclase. A-350619 increased V(max) from 0.1 to 14.5 micromol/min/mg (145 fold increase), and lowered K(m) from 300 to 50 microM (6 fold decrease). When YC-1 (another sGC activator) and A-350619 were combined, a 156 fold increase in V(max) and a 5 fold decrease in Km were observed, indicating that the modulation of the enzyme brought about by YC-1 and A-350619 are not additive, suggesting a common binding site. Activation of soluble guanylyl cyclase by A-350619 was partially inhibited by ODQ, a specific inhibitor of soluble guanylyl cyclase by oxidation of the enzyme heme. YC-1 and A-350619 after pre-treatment with N-omega-nitro-L-arginine, an NO-synthase inhibitor, relaxed cavernosum tissue strips in a dose-dependent manner with EC(50) of 50 microM and 80 microM, respectively. Addition of SNP potentiated the relaxation effect of YC-1 and A-350619, shifting the dose-response curve to the left to 3 microM and 10 microM, respectively. Consistent with its biochemical activity, A-350619 (1 micromol/kg) alone induced penile erection in a conscious rat model. Activation of soluble guanylyl cyclase in cavernosum tissue as an alternate method of enhancing the effect of NO may provide a novel treatment of sexual dysfunction.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, AP9, Room 1125, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6119, USA. loan.n.miller@abbott.com
authors.forename: Loan N
authors.initials: LN
authors.lastname: Miller
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Renjie
authors.initials: R
authors.lastname: Chang
authors.forename: Teodozyi
authors.initials: T
authors.lastname: Kolasa
authors.forename: Robert B
authors.initials: RB
authors.lastname: Moreland
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000096:biosynthesis*; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D010410:Penile Erection / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D018411:Spodoptera / Q000201:enzymology
chemical_list: C470768:3-(2-(4-chlorophenylsulfanyl)phenyl)-N-(4-dimethylaminobutyl)acrylamide; D000178:Acrylamides; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007191:Indazoles; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D006162:Guanylate Cyclase; D006152:Cyclic GMP