Synthesis of 2-Piperazinylbenzothiazole and 2-Piperazinylbenzoxazole Derivatives with 5-HT3 Antagonist and 5-HT4 Agonist Properties

Abstract

New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle 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 weaker than the typical 5-HT3 receptor antagonist as displacers of [3H]BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like the prokinetic agent cisapride, some of the new compounds enhanced gastric emptying in rats. Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation. The latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 5-methoxytryptamine. Compound 2f appears to show a promising pharmacological profile as a potential gastrokinetic agent.

Activity‐dependent bidirectional regulation of GABAA receptor channels by the 5‐HT4 receptor‐mediated signalling in rat prefrontal cortical pyramidal neurons

“…The enhancement of peak GABA A currents by RS67506 was 18.1 ± 8.6 % (mean ± s.d ., n = 9, P < 0.01, Mann‐Whitney U test), and the reduction of peak GABA A currents by RS67506 was 13.7 ± 5.8 % ( n = 11, P < 0.01). Another 5‐HT 4 receptor agonist 2‐[1‐(4‐piperonyl)piperaziny] benzothiazole (20 μ m , Monge et al 1994) gave similar effects: enhancing ( n = 4) or reducing GABA A currents ( n = 5) by amounts similar to those found with 5‐MT treatment (data not shown).…”

Activity-dependent bidirectional regulation of GABAA receptor channels by the 5-HT4 receptor-mediated signalling in rat prefrontal cortical pyramidal neurons

“…Another 5-HT 4 receptor agonist 2-[1-(4-piperonyl)piperaziny] benzothiazole (20 mM, Monge et al 1994) gave similar effects: enhancing (n = 4) or reducing GABA A currents (n = 5) by amounts similar to those found with 5-MT treatment (data not shown).…”

Review of 5-HT4R Ligands: State of Art and Clinical Applications

“…16) A series of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives, including 80, which display dual 5-HT 3 R antagonist and 5-HT 4 R agonist activity with little or no effect at 5-HT 2 , 5-HT 1 or dopamine D 2 receptors, was described [133]. Pyrrolobenzoxazine derivatives like 81 appeared in a patent [134], described as having dual affinities for 5-HT 3 R (antagonists) and 5-HT 4 R (agonists).…”