Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

Abstract

Background: 5-HT 4 receptor (5-HT 4 R) 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-HT 4 R agonists promote intestinal motility. Methods: Non-absorbed 5-HT 4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT 4 R 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-HT 4 R. 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-HT 4 R antagonist and were not detected in 5-HT 4 R 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-HT 4 R 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.

Direct and indirect mechanisms by which the gut microbiota influence host serotonin systems

“…14 Stimulation of 5-HT 4 Rs produces prokinetic effects, 15 and 5-HT 4 R agonists promote colonic propulsive motility. 14,43 Tryptamine-induced activation of 5-HT 4 Rs accelerates gut transit through increased secretion by intestinal epithelial cells. 42 Tryptamine can also, acting as a 5-HT 4 R agonist, stimulate mucus release from goblet cells and prevent epithelial barrier disruption, 44 which has important implications for gut-derived inflammatory conditions such as irritable bowel syndrome.…”

“…5‐HT 4 Rs are G‐protein‐coupled receptors that are expressed in the epithelium of the GI tract, with the greatest level of expression in the distal colon 14 . Stimulation of 5‐HT 4 Rs produces prokinetic effects, 15 and 5‐HT 4 R agonists promote colonic propulsive motility 14,43 …”

Enterochromaffin Cells–Gut Microbiota Crosstalk: Underpinning the Symptoms, Pathogenesis, and Pharmacotherapy in Disorders of Gut-Brain Interaction

“…(7) The mode of administration and the pharmacokinetics of therapeutic agents are critical features for clinical outcomes. 22,23 The therapeutic modalities of enhancing the selectivity and specificity of the drugs for the gut cells are another approach to achieve better target efficacy. 24 A further challenge for achieving the prokinetic effect is still incomplete, which requires activation of both luminal and myenteric circuitry 5-HT receptor 4 (5-HT 4 R).…”

Tryptophan‐synthesizing bacteria enhance colonic motility

“…3 Notably, 5-HT 4 R stimulation produces prokinetic effects, and agonists at the 5-HT 4 R promote colonic propulsive motility and are used to treat constipation. 2,3,17 Thus, we sought to further elucidate the mechanisms by which B. subtilis R0179 exerts prokinetic effects and investigate whether the 5-HT 4 R plays a role.…”