Acrylamide analog as a novel nitric oxide-independent soluble guanylyl cyclase activator.
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 a cascade that results in physiological processes such as smooth muscle relaxation, neurotransmission, and inhibition of platelet aggregation. Here we examine a representative of the novel class sCG activators, A-778935 ((+/-)-cis-3-[2-(2,2-dimethyl-propylsulfanyl)-pyridin-3-yl]-N-(3-hydroxy-cyclohexyl)-acrylamide). A-778935 activated sGC synergistically with sodium nitroprusside (SNP) over a wide range of concentration, inducing up to 420-fold activation. A specific inhibitor of sGC, ODQ (1H-[1,2,4]-oxadiazolo[4,3-alpha]quinoxalin-1-one), did not block basal sGC activity, but competitively inhibited the activation by A-778935. A-778935, with or without SNP, did not activate heme-deficient sGC, indicating that the activation of sGC by A-778935 is fully heme-dependent. A-778935 increased intracellular cGMP level dose-dependently in smooth muscle cells. In the presence of 1 microM SNP, a lower concentration of A-778935 increased cGMP than A-778935 alone, and the cGMP concentration reached the same level at 100 microM of A-778935. A-778935 relaxed cavernosum tissue strips in a dose-dependent manner; and in the presence of 1 microM SNP, A-778935 relaxed the strips more potently, shifting the dose-response curve to the left. This novel activator of sGC may have potential efficacy for the treatment of a variety of disorders associated with reduced NO signaling.
Nakane
Masaki
M
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, USA. masaki.nakane@abbott.com
Kolasa
Teodozyi
T
Chang
Renjie
R
Miller
Loan N
LN
Moreland
Robert B
RB
Brioni
Jorge D
JD
D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002460:Cell Line; D003001:Cloning, Molecular; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
C515661:3-(2-(2,2-dimethylpropylsulfanyl)pyridin-3-yl)-N-(3-hydroxycyclohexyl)acrylamide; D000178:Acrylamides; D020536:Enzyme Activators; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP