SB‐207266: 5‐HT₄ receptor antagonism in human isolated gut and prevention of 5‐HT‐evoked sensitization of peristalsis and increased defaecation in animal models

Abstract

SB-207266 is a new 5-HT4 receptor antagonist which in a pilot study reduced the symptoms of irritable bowel syndrome. To help validate this and further studies, we examined the ability of SB-207266 to antagonize at the human 5-HT4 receptor (human isolated intestine) and to affect the mechanisms of peristalsis (guinea-pig isolated ileum) and defaecation (conscious, fed mice). In the human intestine, the potency of 5-HT4 receptor antagonism (pKB 9.98) was similar to that previously demonstrated using a guinea-pig model of the receptor, validating the use of SB-207266 in clinical trials. In each of the animal models, SB-207266 did not affect normal patterns of intestinal motility measured in the absence of exogenous 5-HT. However, SB-207266 10-1000 pM concentration-dependently antagonized the ability of 5-HT (0.1 microM) to sensitize the peristaltic reflex and lower the distension threshold at which peristalsis was evoked. In mice, oral or subcutaneous (s.c.) doses of SB-207266 dose-dependently prevented the ability of the 5-HT precursor, 5-hydroxytryptophan (5-HTP, 10 mg kg-1 s.c.) to increase both the rate of defaecation of formed faecal pellets and their fluid content. SB-207266 was maximally active at 10 micrograms kg-1 s.c. and 1000 micrograms kg-1 p.o. SB-207266 may therefore represent a new class of therapeutic agent, capable of preventing the actions of an important sensitizer of gut function.

Serotonin and Its Role in Colonic Function and in Gastrointestinal Disorders

“…35,49,50 Overall, animal and human studies have shown that 5-HT 4 receptor antagonists have a minimal effect on normal healthy volunteers, but do ameliorate the effects of administered 5-HT or 5-HT 4 receptor agonists. 49,51 These data suggest that piboserod works in disorders of excess 5-HT but not in the healthy population. There is concern that piboserod may cause atrial fibrillation because of its effects on atrial 5-HT 4 receptors.…”

Luminally released serotonin stimulates colonic motility and accelerates colonic transit in rats

“…Not only 5-HT 3 receptors but also 5-HT 4 receptors mediate colonic motility and fecal pellet output in response to endogenous or exogenous 5-HT in rodents (2,18,22,24,39,42,43). In mouse, rat, and human intestine, the peristaltic reflex is initiated by mucosal release of 5-HT and activation of 5-HT 4 receptors on CGRP sensory neurons, which is relayed to VIP/nitric oxide inhibitory motor neurons and to ACh/tachykinin excitatory motor neurons (17) Further studies are needed to address whether 5-HT 4 receptors are involved in mediating the stimulation of colonic motility in response to restraint stress in rats.…”

Peripheral peptide YY inhibits propulsive colonic motor function through Y2 receptor in conscious mice

“…To address whether PYY 3-36 -induced suppression of the colonic response to a novel environmental stress involves activation of corticotrophin-releasing factor receptor 2 (CRF 2 ) inhibitory pathways (42), we used the CRF 2 antagonist, astressin 2 -B (51). Next, we investigated whether PYY and PYY inhibitory action can modulate the prokinetic effect of cholinergic and serotonergic transmitters (22,64) using exogenous serotonin (5-HT) precursor, 5-hydroxytryptophan (5-HTP) that mimics a state of endogenous 5-HT production and release (52) and the long-acting muscarinic agonist, bethanechol. The role of Y 2 in mediating PYY inhibitory action was further assessed pharmacologically with the selective Y 2 antagonist, BIIE0246 (3,12), and potential site of action by assessing the expression of Y 2 receptor at the gene and protein levels in the mice colon.…”