Prokinetic effects of a new 5-HT4 agonist, YKP10811, on gastric motility in dogs.

Abstract

BACKGROUND AND AIM:

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-HT4 receptor 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-HT4 mechanism 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: Jieyun Yin, Xiaohong Xu, Gengqing Song, Hyun Sil Han, Hong Wook Kim, Jiande D Z Chen
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 32 Issue 3 Pg. 625-630 (Mar 2017) ISSN: 1440-1746 [Electronic] Australia
• PMID: 27418395 (Publication Type: Journal Article)
• Copyright: © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Chemical References

• Benzamides
• Carbamates
• Serotonin 5-HT4 Receptor Agonists
• carbamic acid 3-(4-((4-amino-5-chloro-2-methoxybenzoylamino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl ester
• Glucagon

Topics

• Administration, Oral
• Animals
• Benzamides (administration & dosage, pharmacology)
• Carbamates (administration & dosage, pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Gastric Emptying (drug effects)
• Gastrointestinal Motility (drug effects)
• Gastroparesis (drug therapy)
• Glucagon (pharmacology)
• Pyloric Antrum (drug effects, physiology)
• Serotonin 5-HT4 Receptor Agonists (administration & dosage, pharmacology)