Antagonistic Activity of Y-25130 on 5-HT3 Receptors

The Japanese Journal of Pharmacology

Michihide Setoguchi¹  Keiichiro Haga¹  Shuzo Takehara¹  Noriko Sato¹  Masamitsu Sakamori¹ 

[1] Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd.

关键词: Y-25130;    5-HT3 receptor;    Heart (isolated);    Ileum (isolated);   

DOI  :  10.1254/jjp.59.443

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(24)Cited-By(18)This paper describes the 5-hydroxytryptamine3 (5-HT3) receptor antagonism of Y-25130 ((±)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3, 4-dihydro-2H-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 [3H]quipazine to 5-HT3 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-HT3 receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine H1 receptors (IC50 = 4.4 μM) but it could not reveal any affinities for the other receptors (5-HT1A, 5-HT2, dopamine D1, dopamine D2, α1-adrenoceptor, α2-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 (pA2 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 (pA2 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-HT3 receptor antagonist.

【 授权许可】

Unknown