SYNTHESIS OF 2-PIPERAZINYLBENZOTHIAZOLE AND 2-PIPERAZINYLBENZOXAZOLE DERIVATIVES WITH 5-HT3 ANTAGONIST AND 5-HT4 AGONIST PROPERTIES

New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivative s were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscl e myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2e and 2f, were more potent than ondansetron in this regard. However, these two compounds were much we aker than the typical 5-HT3 receptor antagonist as displacers of [H-3] BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like th e prokinetic agent cisapride, some of the new compounds enhanced gastr ic emptying in rats. Compound 2f not only markedly enhanced gastric em ptying but was also a potent agonist at the isolated rat oesophageal t unics muscularis mucosae, a preparation sensitive to 5-HT4 receptor st imulation, and enhanced the twitch response in the LMMP preparation. T he latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 6-methoxytryptamine Compound 2f appe ars to show a promising pharmacological profile as a potential gastrok inetic agent.