title: Prokinetic effects of a new 5-HT4agonist, YKP10811, on gastric motility in dogs.
abstract: OBJECTIVE
  Prokinetics have been considered the first-line medicine for treating delayed gastric emptying. The aim of this study was to explore the effects and mechanisms of a new 5-HT4receptor agonist, YKP10811, on gastric motility in dogs.
  
  
  METHODS
  Four experiments were performed in dogs: (i) dose-response effects of YKP10811 on liquid gastric emptying; (ii) effects and mechanisms of YKP10811 on solid gastric emptying delayed by glucagon; (iii) effects of low-dose YKP10811 on antral contractions; and (iv) effects of low-dose YKP10811 on gastric accommodation.
  
  
  RESULTS
  No adverse events or cardiac dysrhythmia was noted. (i) High-dose YKP10811 (30 mg/kg) accelerated liquid gastric emptying from 15 to 90 min without inducing adverse events or cardiac dysrhythmia. YKP10811 at low doses (0.3, 1, and 3 mg/kg) accelerated gastric emptying in a dose-dependent manner. (ii) YKP10811 (0.1 mg/kg), but not tegaserod (0.3 mg/kg), significantly accelerated glucagon-induced delayed gastric emptying of solid, and the effect was completely blocked by GR113808. (iii) YKP10811 (0.3 mg/kg) enhanced antral contractions. (iv) YKP10811 did not alter gastric accommodation.
  
  
  CONCLUSIONS
  YKP10811 seems to improve antral contractions and accelerate gastric emptying without altering gastric accommodation in dogs via the 5-HT4mechanism and is substantially more potent than tegaserod. No adverse events were noted at a dose 300 times the lowest effective dose. YKP10811 may have a therapeutic potential for gastroparesis.
authors.affiliation: Division of Gastroenterology, University of Texas Medical Branch, Galveston, Texas, USA.|VA Medical Center, Veterans Research and Education Foundation, Oklahoma, Oklahoma, USA.
authors.forename: Jieyun
authors.initials: J
authors.lastname: Yin
authors.affiliation: VA Medical Center, Veterans Research and Education Foundation, Oklahoma, Oklahoma, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Xu
authors.affiliation: VA Medical Center, Veterans Research and Education Foundation, Oklahoma, Oklahoma, USA.
authors.forename: Gengqing
authors.initials: G
authors.lastname: Song
authors.affiliation: Non-Clinical Development Group, Division of Pharm Development, SK Life Science, Inc., Fair Lawn, New Jersey, USA.
authors.forename: Hyun Sil
authors.initials: HS
authors.lastname: Han
authors.affiliation: Non-Clinical Development Group, Division of Pharm Development, SK Life Science, Inc., Fair Lawn, New Jersey, USA.
authors.forename: Hong Wook
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Division of Gastroenterology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Jiande D Z
authors.initials: JD
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D018589:Gastroparesis / Q000188:drug therapy; D005934:Glucagon / Q000494:pharmacology; D011706:Pyloric Antrum / Q000187:drug effects / Q000502:physiology; D058828:Serotonin 5-HT4 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D002219:Carbamates; D058828:Serotonin 5-HT4 Receptor Agonists; C000600155:carbamic acid 3-(4-((4-amino-5-chloro-2-methoxybenzoylamino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl ester; D005934:Glucagon
keywords: 5-HT4 receptor agonists; gastric emptying; gastrointestinal motility; gastroparesis