title: An in vitro investigation of the cardiovascular effects of the 5-HT(4) receptor selective agonists, velusetrag and TD-8954.
abstract: The 5-HT(4) receptor agonists, and gastrointestinal (GI) prokinetic agents, cisapride and tegaserod, lack selectivity for the 5-HT(4) receptor. Cisapride is a potent human ether-à-go-go-related gene (hERG) potassium channel inhibitor while cisapride and tegaserod have significant affinity for 5-HT(1) and 5-HT(2) receptor subtypes. Marketing of both compounds was discontinued due to cardiovascular concerns (cardiac arrhythmias with cisapride and ischemic events with tegaserod). The reported association of tegaserod with ischemia has been postulated to involve coronary artery constriction or augmentation of platelet aggregation. This in vitro study investigated the effects of two of the new generation of highly selective 5-HT(4) receptor agonists, velusetrag and TD-8954, on canine, porcine and human coronary artery tone, human platelet aggregation and hERG potassium channel conductance. No significant off-target actions of velusetrag or TD-8954 were identified in these, and prior, studies. While cisapride inhibited potently the hERG channel currents, tegaserod failed to affect platelet aggregation, and had only a small contractile effect on the canine coronary artery at high concentrations. Tegaserod inhibited the 5-HT-induced contractile response in the porcine coronary artery. New generation 5-HT(4) receptor agonists hold promise for the treatment of patients suffering from GI motility disorders with a reduced cardiovascular risk.
authors.affiliation: Theravance, Inc., South San Francisco, CA 94080, USA. dbeattie@theravance.com
authors.forename: D T
authors.initials: DT
authors.lastname: Beattie
authors.forename: D L
authors.initials: DL
authors.lastname: Higgins
authors.forename: M P
authors.initials: MP
authors.lastname: Ero
authors.forename: S M
authors.initials: SM
authors.lastname: Amagasu
authors.forename: R G
authors.initials: RG
authors.lastname: Vickery
authors.forename: K
authors.initials: K
authors.lastname: Kersey
authors.forename: A
authors.initials: A
authors.lastname: Hopkins
authors.forename: J A M
authors.initials: JA
authors.lastname: Smith
mesh_terms: D000328:Adult; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D016466:CHO Cells; D020117:Cisapride / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology*; D013552:Swine
chemical_list: C581614:4-((4-((2-isopropyl-1H-benzoimidazole-4-carbonyl)amino)methyl)piperidin-1-ylmethyl)piperidine-1-carboxylic acid methyl ester; D053961:Azabicyclo Compounds; D001562:Benzimidazoles; D051638:Ether-A-Go-Go Potassium Channels; D007211:Indoles; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; C533727:TD-5108; C105050:tegaserod; D020117:Cisapride