Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect.

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D, D, 5-HT, 5-HT and H, a moderate affinity for 5-HT, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT, adrenergic α and H). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.