Acrylamide Analog as a Novel Nitric Oxide-Independent Soluble Guanylyl Cyclase Activator
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- Nakane Masaki
- Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, USA
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- Kolasa Teodozyi
- Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, USA
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- Chang Renjie
- Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, USA
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- Miller Loan N.
- Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, USA
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- Moreland Robert B.
- Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, USA
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- Brioni Jorge D.
- Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, USA
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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 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-α]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 μM SNP, a lower concentration of A-778935 increased cGMP than A-778935 alone, and the cGMP concentration reached the same level at 100 μM of A-778935. A-778935 relaxed cavernosum tissue strips in a dose-dependent manner; and in the presence of 1 μM 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.<br>
Journal
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- Journal of Pharmacological Sciences
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Journal of Pharmacological Sciences 102 (2), 231-238, 2006
The Japanese Pharmacological Society
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Details 詳細情報について
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- CRID
- 1390001205177660288
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- NII Article ID
- 10020345739
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- NII Book ID
- AA11806667
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- ISSN
- 13478648
- 13478613
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- NDL BIB ID
- 8094957
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- CiNii Articles
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- Abstract License Flag
- Disallowed