YKP10811: A Novel 5-HT4 Partial Agonist for Visceral Hypersensitivity in Rats

This study investigates the impact of YKP10811, a novel 5-HT4 receptor partial agonist, on rat models affected by colorectal hypersensitivity due to distension. The research involved both male and female rats subjected to colorectal distension (CRD) after infusion with trinitrobenzene sulfonic acid (TNBS) and exposure to acute or chronic stress. Pain was measured by electromyographic (EMG) responses to CRD, and colonic tone changes were also assessed. The study compared YKP10811's effects to those of tegaserod and evaluated the potential for pharmacological tachyphylaxis in TNBS-induced hypersensitivity.

Key findings indicate that YKP10811, at a dosage of 30 mg/kg, did not alter baseline sensitivity or tone but effectively reduced hypersensitivity caused by TNBS. This effect was negated by the 5-HT4 receptor antagonist GR113808. YKP10811 mitigated acute stress-induced colonic hypersensitivity but had no effect on chronic stress-induced hypersensitivity. Notably, YKP10811, unlike tegaserod, decreased TNBS-induced hypersensitivity even after a week of treatment.

The study concludes that YKP10811 demonstrates pain-relieving properties in conditions of inflammation and acute stress-related colonic hypersensitivity via 5-HT4 receptors. Unlike tegaserod, YKP10811 retains its efficacy with repeated use, suggesting its potential as a new therapeutic option for IBS-C patients.