Antagonistic Activity of Y-25130 on 5-HT3 Receptors.

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概要

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• This paper describes the 5-hydroxytryptamine<SUB>3</SUB> (5-HT<SUB>3</SUB>) receptor antagonism of Y-25130 ((±)-<I>N</I>-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3, 4-dihydro-2<I>H</I>-1, 4-benzoxazine-8-carboxamide monohydrochloride) in the rat cerebral cortex, isolated rabbit heart and isolated guinea pig ileum. In an in vitro binding assay, Y-25130 inhibited the specific binding of [<SUP>3</SUP>H]quipazine to 5-HT<SUB>3</SUB> receptors at the synaptic membranes of the rat cerebral cortex with a K; value of 2.9 nM, the same as that of ondansetron. Metoclopramide, 5-HT and 2-methyl-5-HT also showed an inhibitory effect, but their affinities for 5-HT<SUB>3</SUB> receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine H<SUB>1</SUB> receptors (IC<SUB>50</SUB> = 4.4 μM) but it could not reveal any affinities for the other receptors (5-HT<SUB>1A</SUB>, 5-HT<SUB>2</SUB>, dopamine D<SUB>1</SUB>, dopamine D<SUB>2</SUB>, α<SUB>1</SUB>-adrenoceptor, α<SUB>2</SUB>-adrenoceptor, muscarine and benzodiazepine) even at a 10 μM concentration. In the isolated rabbit heart, Y-25130 antagonized the indirect sympathomimetic responses to 5-HT (pA<SUB>2</SUB> value = 10.06) and this effect was more potent than that of metoclopramide. In the isolated longitudinal smooth muscle of the guinea pig ileum, concentration-contraction effect curves for 5-HT were biphasic in the presence of ketanserin. Y-25130 shifted to the right only in the second phase of concentration-effect curves for 5-HT (pA<SUB>2</SUB> value = 7.04) and its activity was more potent than that of metoclopramide. These results indicate that Y-25130 is a potent and selective 5-HT<SUB>3</SUB> receptor antagonist.

• 公益社団法人 日本薬理学会の論文

著者

• Sakamori Masamitsu

  Research Laboratories Yoshitomi Pharmaceutical Industries Ltd.

• Takehara Shuzo

  Research Laboratories Yoshitomi Pharmacoceutical Industries Ltd.

• Setoguchi Michihide

  Research Laboratories Yoshitomi Pharmacoceutical Industries Ltd.

• Sato Noriko

  Research And Development Center Toshiba Corporation

• Sakamori Masamitsu

  Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd.

• Haga Keiichiro

  Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd.

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