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-HT1A, 5-HT2A and H3 receptors, and low efficacy at the off-target receptors (5-HT2C, 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.
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