Synthesis, structure-activity relationships, and biological evaluation of a series of benzamides as potential multireceptor antipsychotics.

Abstract In the present study, a series of benzamides, endowed with potent dopamine D 2 , serotonin 5-HT 1A and 5-HT 2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(4-(4-(6-fluorobenzo[ d ]isoxazol-3-yl)-piperidin-1-yl)butoxy)- N -methylbenzamide ( 21 ) and its fluoro-substituted analogue ( 22 ) held the best pharmacological binding profiles. They not only presented potent activities for D 2 , 5-HT 1A , and 5-HT 2A receptors, but were also endowed with low activities for 5-HT 2C , H 1 receptors and hERG channels, suggesting a low propensity of inducing weight gain and QT prolongation. In animal models, compounds 21 and 22 reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. It thus provides potential candidates for further preclinical studies.