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

A series of benzamide derivatives possessing potent dopamine D 2 , serotonin 5‐HT 1A , and 5‐HT 2A 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 D 2 , 5‐HT 1A , and 5‐HT 2A receptors, but was also endowed with low to moderate activities for the 5‐HT 2C , H 1 , and M 3 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.