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

• Published in: Japanese journal of pharmacology 1992, Vol.59 (3), p.357-364
• Main Authors: Miki, Ichiro, Kishibayashi, Nobuyuki, Nonaka, Hiromi, Ohshima, Etsuo, Takami, Hitoshi, Obase, Hiroyuki, Ishii, Akio
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzimidazoles - pharmacology; Benzoxepins - pharmacology; Biological and medical sciences; Blood Platelets - drug effects; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Guinea Pigs; Humans; Hydrazines - pharmacology; In Vitro Techniques; Kinetics; KW-3635; Medical sciences; Pharmacology. Drug treatments; Platelets; Prostaglandin Endoperoxides, Synthetic - pharmacology; Radioligand Assay; Rats; Receptors, Thromboxane - drug effects; Respiratory system; Species Specificity; Thromboxane A2 - antagonists & inhibitors; Thromboxane A2 antagonist; Thromboxane A2/prostaglandin H2 receptors; Tritium; Vasoconstrictor Agents - pharmacology
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1016/S0021-5198(19)37633-4

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-1-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.