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

A series of benzamide derivatives possessing potent dopamine D₂ , 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 D₂ , 5-HT_1A , and 5-HT_2A receptors, but was also endowed with low to moderate activities for the 5-HT_2C , 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.