Derivatives of benzotetrazine-1,3-dioxide are new NO-donors, activators of soluble guanylate cyclase, and inhibitors of platelet aggregation.
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 microM concentration and the activity increase was 4.5-, 15.0-, and 8.2-fold in the presence of 20 microM dithiothreitol and 11.3-, 31.6-, and 20.5-fold, respectively, in the presence of added glutathione (100 microM). The NO-dependent mechanism of benzotetrazine-1,3-dioxide nitroderivative-induced activation of soluble guanylate cyclase (in the presence of 100 microM glutathione) was confirmed by the inhibition (by 78%) of 7-nitrobenzotetrazine-1,3-dioxide (10 microM)-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 microM) and by the inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 0.3 microM) of 5-nitro-, 7-nitro-, and 5,7-dinitrobenzotetrazine-1,3-dioxides (10 microM)-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 microM 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.
Pyatakova
N V
NV
Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Pogodinskaya ul. 10, Moscow, 119992 Russia.
Khropov
Yu V
YV
Churakov
A M
AM
Tarasova
N I
NI
Serezhenkov
V A
VA
Vanin
A F
AF
Tartakovsky
V A
VA
Severina
I S
IS
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D001372:Aza Compounds / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*
D001372:Aza Compounds; D006571:Heterocyclic Compounds; D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D006162:Guanylate Cyclase