Prokinetic actions of luminally acting 5-HT4 receptor agonists

Background: 5-HT4 receptor (5-HT4R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT(4)Rs have limited their use. Since 5-HT(4)Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT4R agonists promote intestinal motility. Methods: Non-absorbed 5-HT4R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT4R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. Key Results: Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT4R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5-HT4R antagonist and were not detected in 5-HT4R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5-HT4R is present in the epithelial layer of the human small and large intestines. Conclusions and Inferences: These findings demonstrated that stimulation of epithelial 5-HT(4)Rs can potentiate propulsive motility and support the concept that mucosal 5-HT(4)Rs could represent a safe and effective therapeutic target for the treatment of constipation.

Automated summary

Stimulation of epithelial 5-HT(4)Rs can enhance propulsive motility, indicating mucosal 5-HT(4)Rs may represent a safe and effective therapeutic target for constipation treatment.