N-{[2-(4-Phenyl-piperazin-1-yl)-ethyl]-phenyl}-arylamides with dopamine D2 and 5-Hydroxytryptamine 5HT(1A) activity: synthesis, testing, and molecular modeling.

The ratio of affinities toward the dopamine D2 and the 5-hydroxytryptamine 5-HT(1A) receptors is one of the important parameters that determine the efficiency of antipsychotic drugs. Here, we present the synthesis of ortho-, meta-, and para-N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-arylamides and their structure-activity relationship studies on dopamine D2 and 5-hydroxytryptamine 5-HT(1A) receptors. It was shown that the biological activity of the described ligands strongly depends on their topology as well as on the nature of the heteroaryl group in the head of the molecules. Docking simulations together with conformational analysis revealed a rational explanation for the ligands' behavior. The molecular model of receptor-ligand interactions described herein provided us with a tool for the rational design of new compounds with a favorable D2/5-HT(1A) profile.