Continuation of structure–activity relationship study of novel benzamide derivatives as potential antipsychotics

Abstract

A series of benzamide derivatives possessing potent dopamine D2, serotonin 5‐HT1A, and 5‐HT2A receptor properties were synthesized and evaluated as potential antipsychotics. Among them, 5‐(4‐(4‐(benzo[d]isothiazol‐3‐yl)piperazin‐1‐yl)butoxy)‐N‐cyclopropyl‐2‐fluorobenzamide (4k) held the best pharmacological profile. It not only exhibited potent and balanced activities for the D2, 5‐HT1A, and 5‐HT2A receptors, but was also endowed with low to moderate activities for the 5‐HT2C, H1, and M3 receptors, suggesting a low propensity for inducing weight gain or diabetes. In animal models, compound 4k reduced phencyclidine‐induced hyperactivity with a high threshold for catalepsy or muscle relaxation induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, 4k was selected as a candidate for further development.