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

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, 3w combines a multi-receptor mechanism with high mixed affinities for D₂, 5-HT_1A, 5-HT_2A and H₃ receptors, and low efficacy at the off-target receptors (5-HT_2C, H₁ and α₁ receptor) and human ether-à-go-go-related gene (hERG) channel. In addition, compound 3w exhibits favorable antipsychotic drug-like activities in in vivo assessment. An animal behavioral study revealed that compound 3w significantly reverses apomorphine-induced climbing and MK-801-induced hyperactivity, and avoidance behavior in the CAR test, with a high threshold for catalepsy. Moreover, compound 3w demonstrates 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, 3w was selected as an antipsychotic candidate for further development.