The in vivo gastrointestinal activity of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity
| Autor: | Patrick P.A. Humphrey, J A M Smith, D. Marquess, J. A. Taylor, C. Sandlund, J.-P. Shaw, David Beattie, Scott R. Armstrong |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Agonist Indoles Tegaserod Intrinsic activity Colon medicine.drug_class Morpholines Guinea Pigs Administration Oral Pharmacology Rats Sprague-Dawley Contractility Serotonin 5-HT4 Receptor Agonists Dogs Esophagus In vivo medicine Animals Gastrointestinal Transit Antrum Cisapride Dose-Response Relationship Drug Chemistry Muscle Smooth General Medicine Mosapride Rats Serotonin Receptor Agonists Benzamides Female Azabicyclo Compounds Muscle Contraction medicine.drug |
| Zdroj: | Naunyn-Schmiedeberg's Archives of Pharmacology. 378:139-147 |
| ISSN: | 1432-1912 0028-1298 |
| DOI: | 10.1007/s00210-008-0281-z |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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