Serotonin (5-HT)3-Receptor Antagonism of 4,5,6,7-Tetrahydrobenzimidazole Derivatives against 5-HT-Induced Bradycardia in Anesthetized Rats.

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概要

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• We investigated the mode of the 5-HT<SUB>3</SUB>-receptor antagonism of 4, 5, 6, 7-tetrahydrobenz-imidazole derivatives, YM060, YM114 (KAE-393), YM-26103-2 and YM-26308-2, against 5-HT-induced transient bradycardia in anesthetized rats. Results were compared with those of ondansetron and granisetron. YM060 (0.03-0.1 μg/kg, i.v.), YM114 (0.03-0.3 μg/kg, i.v.), YM-26103-2 (0.01-0.03 μg/kg, i.v.), YM-26308-2(0.01-0.03 μg/kg, i.v.) and granisetron (0.3-3 μg/kg, i.v.) displaced the 5-HT dose-response curve to the right, with apparent DR<SUB>2</SUB> values of 0.068, 0.068, 0.019, 0.011 and 0.69 μg/kg, i.v., respectively. Higher doses of these compounds inhibited 5-HT-induced bradycardia with a reduced maximal response. In contrast, ondansetron displaced the 5-HT dose-response curve to the right without affecting the maximal response. Judged by the apparent DR<SUB>2</SUB> values, YM060, YM114, YM-26103-2 and YM-26308-2 were approximately 13, 13, 50 and 79 times more potent than ondansetron, respectively, whereas granisetron was equipotent to ondansetron. Single i.v. doses of YM060 and granisetron inhibited 5-HT-induced bradycardia significantly longer than ondansetron. Moreover, inhibitory effects of p.o. doses of YM060(3 μg/kg), YM 114(80 μg/kg), YM-26103-2(12 μg/kg), YM-26308-2(5 μg/kg) and granisetron (250 μg/kg) on the von Bezold-Jarisch reflex lasted for 3-6 hr, whereas ondansetron (700 μg/kg, p.o.) antagonized 5-HT<SUB>3</SUB> receptors for only 1 hr. In isolated guinea pig colon, the inhibitory effect of YM-compounds on 5-HT-induced contraction persisted significantly longer than those of ondansetron and granisetron after washout of the bath containing compounds. These results suggest that YM-compounds are highly potent 5-HT<SUB>3</SUB>-receptor antagonists. Furthermore, non-competitive 5-HT<SUB>3</SUB>-receptor antagonism of YM-compounds against the von Bezold-Jarisch reflex at higher doses may be reflected in their slow dissociation from the 5-HT<SUB>3</SUB> receptor, and that of granisetron may be reflected in its slow metabolism in anesthetized rats.

• 公益社団法人 日本薬理学会の論文

著者

• Miyata Keiji

  Neuroscience And Gastrointestinal Research Laboratory Institute For Drug Discovery Research Yamanouc

• Tsutsumi Rie

  Neuroscience Research Pharmacology Laboratiries Institute For Drug Discavery Research Yamanouchi Pha

• NISHIDA Akito

  Neuroscience

• Yamano Mayumi

  Neuroscience And Gastrointestinal Research Laboratories Institute For Drug Discovery Research Yamano

• Honda Kazuo

  Neuroscience And Gastrointestinal Research Laboratory Institute For Drug Discovery Research Yamanouc

• Ito Hiroyuki

  Neuroscience And Gastrointestinal Research Laboratory Institute For Drug Discovery Research Yamanouc

• Yuki Hidenobu

  Neuroscience & Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Kamato Takeshi

  Neuroscience & Gastrointestinal Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Kamato Takeshi

  Neuroscience & Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Nishida Akito

  Neuroscience & Gastrointestinal Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Yamano Mayumi

  Neuroscience & Gastrointestinal Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Tsutsumi Rie

  Neuroscience & Gastrointestinal Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Miyata Keiji

  Neuroscience & Gastrointestinal Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Miyata Keiji

  Neuroscience & Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

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• Serotonin (5-HT)3-Receptor Antagonism of 4,5,6,7-Tetrahydrobenzimidazole Derivatives against 5-HT-Induced Bradycardia in Anesthetized Rats.

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