title: The in vitro pharmacological profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity.
abstract: The in vitro pharmacological profile of TD-5108, a novel, selective 5-HT(4) receptor agonist, was compared to that of clinically efficacious gastroprokinetic 5-HT(4) receptor agonists. TD-5108 produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5-HT(4(c)) (h5-HT(4(c))) receptor (pEC(50) = 8.3) and 5-HT(4) receptor-mediated relaxation of the rat esophagus (pEC(50) = 7.9) and contraction of the guinea pig colon (pEC(50) = 7.9). In all in vitro assays, TD-5108 was a high intrinsic activity agonist, unlike tegaserod, mosapride, and cisapride which, in the majority of test systems, had lower intrinsic activity. TD-5108 had high affinity (pK (i) = 7.7) and selectivity (> or =25-fold) for h5-HT(4(c)) receptors over other biogenic amine receptors. TD-5108 was >500-fold selective over other 5-HT receptors (including h5-HT(2B) and h5-HT(3A)) and, at 3 microM, had no effect on human ether-à-go-go-related gene K+ channels. In conclusion, TD-5108 is a selective 5-HT(4) receptor agonist in vitro. The high intrinsic activity and preferential binding of TD-5108 to 5-HT4 over other 5-HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility.
authors.affiliation: Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA. jsmith@theravance.com
authors.forename: J A M
authors.initials: JA
authors.lastname: Smith
authors.forename: D T
authors.initials: DT
authors.lastname: Beattie
authors.forename: D
authors.initials: D
authors.lastname: Marquess
authors.forename: J P
authors.initials: JP
authors.lastname: Shaw
authors.forename: R G
authors.initials: RG
authors.lastname: Vickery
authors.forename: P P A
authors.initials: PP
authors.lastname: Humphrey
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D020117:Cisapride / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D053961:Azabicyclo Compounds; D001549:Benzamides; D051638:Ether-A-Go-Go Potassium Channels; D007211:Indoles; D009025:Morpholines; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; C533727:TD-5108; D044422:Receptors, Serotonin, 5-HT4; C105050:tegaserod; D000242:Cyclic AMP; C062720:mosapride; D020117:Cisapride