ME-3412

Abstract  Therapeutic use of 5‐hydroxytryptamine 3 (5‐HT3) receptor antagonists for diarrhoea‐predominant irritable bowel syndrome may be accompanied by constipation. We hypothesized that ME3412, 5‐chloro‐2‐(1,4‐diazacycloheptan‐1‐yl)‐7‐methylbenzoxazole, a novel partial agonist of the 5‐HT3 receptor, would minimize constipation without reducing antidiarrhoeal activity. Receptor binding studies showed that ME3412 is highly selective for the human 5‐HT3 receptor (Ki = 1.51 nmol L−1). A 5‐HT3 receptor agonist, 2‐methyl‐5‐HT, caused contractile response in the isolated guinea‐pig ileum and accelerated secretion in the guinea‐pig colonic mucosal preparation. ME3412 and 5‐HT3 receptor antagonist, alosetron, antagonized the 2‐methyl‐5‐HT‐induced responses with similar potency in insurmountable and surmountable manner, respectively. ME3412 caused weak agonism in isolated ileum strips and also in the colonic mucosa with intrinsic activity of 0.09 and 0.59, respectively. In conscious dogs, alosetron (3 μg kg−1 i.v.) suppressed the migrating motor complex (MMC), whereas a relatively high dose (300 μg kg−1) of ME3412 was required for inhibition of MMC. ME3412 and alosetron suppressed 5‐HT induced‐diarrhoea in mice. In contrast, ME3412 did not significantly affect colonic propulsion compared with alosetron. These results imply that the partial agonist may relieve diarrhoea with low risk of inducing constipation.