Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics

A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D₂and D₃, and serotonin 5-HT_1Aand 5-HT_2Areceptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D₂, D₃, 5-HT_1A, and 5-HT_2Areceptors, together with a 20-fold selectivity for the D₃versus D₂subtype, and a low affinity for muscarinic M₁(reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.