Prokinetic effects of a new 5‐HT 4 agonist, YKP10811, on gastric motility in dogs

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‐HT 4 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‐HT 4 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.