Synthesis and biological evaluation of a new class of multi-target heterocycle piperazine derivatives as potential antipsychotics

Abstract

In this study, we designed and synthesized a novel series of multi-receptor ligands as polypharmacological antipsychotic agents by using a multi-receptor affinity strategy. Among them,3wcombines a multi-receptor mechanism with high mixed affinities for D2, 5-HT1A, 5-HT2Aand H3receptors, and low efficacy at the off-target receptors (5-HT2C, H1and α1receptor) and human ether-à-go-go-related gene (hERG) channel. In addition, compound3wexhibits favorable antipsychotic drug-like activities inin vivoassessment. An animal behavioral study revealed that compound3wsignificantly reverses apomorphine-induced climbing and MK-801-induced hyperactivity, and avoidance behavior in the CAR test, with a high threshold for catalepsy. Moreover, compound3wdemonstrates memory enhancement in a novel object recognition task and low liabilities for weight gain and hyperprolactinemia in a long-term metabolic adverse effects model. Thus,3wwas selected as an antipsychotic candidate for further development.