title: The in vivo gastrointestinal activity of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity.
abstract: The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT(4) 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-HT(4) receptor agonist, TD-5108, demonstrates robust in vivo activity in the guinea pig, rat and dog gastrointestinal tracts.
authors.affiliation: Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA. dbeattie@theravance.com
authors.forename: D T
authors.initials: DT
authors.lastname: Beattie
authors.forename: S R
authors.initials: SR
authors.lastname: Armstrong
authors.forename: J P
authors.initials: JP
authors.lastname: Shaw
authors.forename: D
authors.initials: D
authors.lastname: Marquess
authors.forename: C
authors.initials: C
authors.lastname: Sandlund
authors.forename: J A M
authors.initials: JA
authors.lastname: Smith
authors.forename: J A
authors.initials: JA
authors.lastname: Taylor
authors.forename: P P A
authors.initials: PP
authors.lastname: Humphrey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D020117:Cisapride / Q000008:administration & dosage / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006168:Guinea Pigs; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D053961:Azabicyclo Compounds; D001549:Benzamides; D007211:Indoles; D009025:Morpholines; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; C533727:TD-5108; C105050:tegaserod; C062720:mosapride; D020117:Cisapride