Pharmacological profile of ME3412, a partial agonist to 5-HT3 receptor

Serotonin-3 (5-HT3) receptor antagonists have been developed as potential drugs for diarrhea-predominant irritable bowel syndrome (IBS), but they have a common side effect of constipation. We expect that a partial agonist to 5-HT3 receptor with a low intrinsic activity would be effective for this disease and avoid the occurrence of constipation. In the present study, we evaluated the pharmacological profile of ME3412, a novel partial agonist of 5-HT3 receptor. The receptor binding studies using membrane fraction showed that ME3412 had highly selective ligand to the 5-HT3 receptor. In an isolated guinea pig ileum, ME3412 antagonized 2-methyl-5-HT induced contractile response in a dose-dependent manner with an insurmountable manner. In contrast, typical 5-HT3 antagonists alosetron and granisetron, antagonized in a surmountable manner. Only ME3412 caused the contractile response in the ileum with intrinsic activity of 0. 09. In a guinea-pig colonic mucosal preparation, ME3412 showed intrinsic activity and insurmountable antagonism for 2-methyl-5HT induced short-circuit current. These results suggest that ME3412 is a selective partial agonist of 5-HT3 receptor to be beneficial in diarrhea-predominant lBS with a low incidence of side effect of constipation.