The in vivo gastrointestinal activity of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity

被引：41

作者：

Beattie, D. T. ^{[1
]}

Armstrong, S. R. ^{[1
]}

Shaw, J. -P. ^{[1
]}

Marquess, D. ^{[1
]}

Sandlund, C. ^{[1
]}

Smith, J. A. M. ^{[1
]}

Taylor, J. A. ^{[2
]}

Humphrey, P. P. A. ^{[1
]}

机构：

[1] Theravance Inc, San Francisco, CA 94080 USA

[2] Drug Res Labs, Camden, NJ 08102 USA

来源：

NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY | 2008年 / 378卷 / 01期

关键词：

gastrointestinal; 5-HT4; TD-5108; tegaserod; pharmacodynamics;

D O I：

10.1007/s00210-008-0281-z

中图分类号：

R9 [药学];

学科分类号：

1007 [药学];

摘要：

The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity, was compared to that of the clinically studied gastrointestinal pro-kinetic agents, tegaserod, cisapride and mosapride. The activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT4 receptor agonist, TD-5108, demonstrates robust in vivo activity in the guinea pig, rat and dog gastrointestinal tracts.

引用

页码：139 / 147

页数：9

共 29 条

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