Derivatives of Benzotetrazine-1,3-dioxide Are New NO-donors, Activators of Soluble Guanylate Cyclase, and Inhibitors of Platelet Aggregation |
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Authors: | N. V. Pyatakova Yu. V. Khropov A. M. Churakov N. I. Tarasova V. A. Serezhenkov A. F. Vanin V. A. Tartakovsky I. S. Severina |
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Affiliation: | (1) Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Pogodinskaya ul. 10, Moscow, 119992, Russia;(2) Department of Bioorganic Chemistry, School of Biology, Lomonosov Moscow State University, Moscow, 119899, Russia;(3) Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky pr. 47, Moscow, 117913, Russia;(4) Institute of Chemical Physics, Russian Academy of Sciences, ul. Kosygina 4, Moscow, 119991, Russia |
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Abstract: | The ability of 5-nitro-, 7-nitro-, and 5,7-dinitrobenzotetrazine-1,3-dioxides to generate nitric oxide (NO) and activate soluble guanylate cyclase was investigated. All of these compounds were found to be thiol dependent NO-donors and guanylate cyclase activators. The maximal stimulatory effect of 5-nitro-, 7-nitro-, and 5,7-dinitrobenzotetrazine-1,3-dioxides was observed at 10 M concentration and the activity increase was 4.5-, 15.0-, and 8.2-fold in the presence of 20 M dithiothreitol and 11.3-, 31.6-, and 20.5-fold, respectively, in the presence of added glutathione (100 M). The NO-dependent mechanism of benzotetrazine-1,3-dioxide nitroderivative-induced activation of soluble guanylate cyclase (in the presence of 100 M glutathione) was confirmed by the inhibition (by 78%) of 7-nitrobenzotetrazine-1,3-dioxide (10 M)-stimulated guanylate cyclase activity in the presence of the NO-scavenger-2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (Carboxy-PTIO, 50 M) and by the inhibition with 1H-[1,2,4 ]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 0.3 M) of 5-nitro-, 7-nitro-, and 5,7-dinitrobenzotetrazine-1,3-dioxides (10 M)-stimulated guanylate cyclase by 34, 69, and 39%, respectively. All compounds used inhibited ADP-induced aggregation of human platelets with IC50 of 10.0, 1.3, and 2.0 M for 5-nitro-, 7-nitro-, and 5,7-dinitrobenzotetrazine-1,3-dioxides, respectively. A clearly defined correlation was established between the ability of the compounds to generate NO, activate soluble guanylate cyclase, and inhibit platelet aggregation. |
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Keywords: | soluble guanylate cyclase nitric oxide derivatives of benzotetrazine-1,3-dioxide platelet aggregation |
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