Effects of KW-3635, a Novel Dibenzoxepin Derivative of a Selective Thromboxane A2 Antagonist, on Human, Guinea Pig and Rat Platelets

[摘要] References(47)Cited-By(10)We examined the binding of [3H]U-46619, a thromboxane A2 agonist, to human and guinea pig platelets and the binding of [3H]SQ 29, 548, a thromboxane A2 antagonist, to human, rat and guinea pig platelets. KW-3635 (sodium (E)-11-[2-(5, 6-dimethyl-l-benzimidazolyl)ethylidene]-6, 11-dihydrodibenz[b, e]oxepin-2-carboxylate monohydrate) concentration-dependently inhibited the [3H]U-46619 binding to human and guinea pig platelets with inhibition constants of 1.2 nM and 2.7 nM, respectively. KW-3635 also potently inhibited the [3H]SQ 29, 548 binding to human and guinea pig platelets with inhibition constants of 1.9 nM and 3.2 nM, respectively. In contrast, KW-3635 was less active against thromboxane A2/prostaglandin H2 receptors in rat platelets with an inhibition constant of 97 nM. KW-3635 at 10-5 M did not antagonize various receptors including prostaglandin E2, prostaglandin I2 and neurotransmitters. In addition, 10-5 M KW-3635 did not alter the prostaglandin D2-induced cAMP accumulation in EBTr cells. KW-3635 was inactive towards thromboxane synthase, cyclooxygenase and prostaglandin I2 synthase up to 10-5 M. KW-3635 slightly inhibited 5-lipoxygenase with an IC50 value of 71 μM. These data indicate that KW-3635 is a potent and selective non-prostanoic thromboxane A2 antagonist, and it can recognize the species differences in thromboxane A2/prostaglandin H2 receptors.

[学科分类] 药理学

[关键词] Thromboxane A2 antagonist;Thromboxane A2/prostaglandin H2 receptors;KW-3635;Platelets