Effects of TAK-480, a Novel Tachykinin NK<SUB>2</SUB>–Receptor Antagonist, on Visceral Hypersensitivity in Rabbits and Ricinoleic Acid–Induced Defecation in Guinea Pigs

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概要

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• TAK-480, 4-(difluoromethoxy)-<I>N</I>-((1<I>R</I>,2<I>S</I>)-2-(((3<I>aR</I>,4<I>R</I>,9<I>bR</I>)-4-(methoxymethyl)-2, 3,3<I>a</I>,4,5,9<I>b</I>-hexahydro-1<I>H</I>-pyrrolo[3,2-<I>c</I>]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK<SUB>2</SUB>–receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK<SUB>2</SUB> receptors with a marked species difference and a 10,000-fold selectivity versus NK<SUB>1</SUB> and NK<SUB>3</SUB> receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK<SUB>2</SUB> receptor–selective agonist beta-Ala<SUP>8</SUP>-NKA(4-10) (<I>β</I>A-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT<SUB>3</SUB>–receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid<I>–</I>induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as <I>β</I>A-NKA in an isolated human colon. In conclusion, the novel NK<SUB>2</SUB>-receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK<SUB>2</SUB> receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients.

• 公益社団法人 日本薬理学会の論文

著者

• Inatomi Nobuhiro

  Pharmaceutical Research Division Takeda Chemical Industries Ltd.

• Toyoda Masao

  Department Of General And Gastroenterological Surgery Osaka Medical College

• Nakamura Akihiro

  Inflammation Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limi

• TANAKA Takahiro

  Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited

• Mizojiri Gaku

  Department Of Surgery Saiseikai-nakatsu Hospital

• Imanishi Akio

  Pharmaceutical Research Division Takeda Pharmaceutical Company Limited

• Tsukimi Yasuhiro

  Pharmaceutical Research Division Takeda Pharmaceutical Company Limited

• Miura Kasei

  Pharmaceutical Research Division Takeda Pharmaceutical Company Limited

• Tanaka Akiko

  Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan

• Nakamura Akihiro

  Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan

• Matsushita Kozo

  Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan

• Matsumoto-Okano Shiho

  Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan

• Inatomi Nobuhiro

  Pharmaceutical Res. Div. Takeda Pharmaceutical Co. Ltd. Jpn

• TANAKA Akiko

  Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited

• Miura Kasei

  Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan

• MATSUSHITA Kozo

  Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited

• Tsukimi Yasuhiro

  Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Japan

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