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

Article abstract of DOI:10.1016/j.bmcl.2016.04.087

In the present study, a series of benzamides, endowed with potent dopamine D₂, 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 D₂, 5-HT_1A, and 5-HT_2A receptors, but were also endowed with low activities for 5-HT_2C, H₁ 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.