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

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概要

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• We examined the binding of [<SUP>3</SUP>H]U-46619, a thromboxane A<SUB>2</SUB> agonist, to human and guinea pig platelets and the binding of [<SUP>3</SUP>H]SQ 29, 548, a thromboxane A<SUB>2</SUB> antagonist, to human, rat and guinea pig platelets. KW-3635 (sodium (<I>E</I>)-11-[2-(5, 6-dimethyl-l-benzimidazolyl)ethylidene]-6, 11-dihydrodibenz[<I>b</I>, <I>e</I>]oxepin-2-carboxylate monohydrate) concentration-dependently inhibited the [<SUP>3</SUP>H]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 [<SUP>3</SUP>H]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 A<SUB>2</SUB>/prostaglandin H<SUB>2</SUB> receptors in rat platelets with an inhibition constant of 97 nM. KW-3635 at 10<SUP>-5</SUP> M did not antagonize various receptors including prostaglandin E<SUB>2</SUB>, prostaglandin I<SUB>2</SUB> and neurotransmitters. In addition, 10<SUP>-5</SUP> M KW-3635 did not alter the prostaglandin D<SUB>2</SUB>-induced cAMP accumulation in EBTr cells. KW-3635 was inactive towards thromboxane synthase, cyclooxygenase and prostaglandin I<SUB>2</SUB> synthase up to 10<SUP>-5</SUP> M. KW-3635 slightly inhibited 5-lipoxygenase with an IC<SUB>50</SUB> value of 71 μM. These data indicate that KW-3635 is a potent and selective non-prostanoic thromboxane A<SUB>2</SUB> antagonist, and it can recognize the species differences in thromboxane A<SUB>2</SUB>/prostaglandin H<SUB>2</SUB> receptors.

• 公益社団法人 日本薬理学会の論文

著者

• Nonaka Hiromi

  Pharmaceutical Research Institute Kyowa Hakko Kogyo Co. Ltd.

• Ohshima Etsuo

  Pharmaceutical Research Center Kyowa Hakko Kogyo Co. Ltd.

• KISHIBAYASHI Nobuyuki

  Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd.,

• Ishii Akio

  Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd.

• Miki Ichiro

  Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd.

• Takami Hitoshi

  Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd.

• Obase Hiroyuki

  Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd.

• Kishibayashi Nobuyuki

  Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd.

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