Dopamine D2 receptor antagonist activity and molecular modeling of certain new cyclohexane derived arylcarboxamides structurally related to Metoclopramide

Abstract

A series of certain new N-{[1-(4-aralkyl/ethylpiperazine-1-yl)cyclohexyl]methyl}arylcarbox- amides 1a-t structurally related to the antiemetic Metoclopramide (I) was synthesized starting from cyclohexanone, N-aralkyl and/or ethylpiperazine, and KCN in the presence of conc. HCl to furnish the carbonitrile derivatives 3a-d. Subsequent reduction of 3a-d produced the respective amines 4a-d which were elaborated to the desired arylcarboxamides 1a-t through amide coupling reactions. The target compounds 1a-t were evaluated for their dopamine D2 receptor antagonistic activity in vivo by measuring their ability to inhibit apomorphine-induced chewing "Zwansgnagen" in rats. Compound 1h (ED50 = 5.94 μmol/kg) is the most active congener being nearly 2-fold more potent than the previously reported cyclohexane-based dopamine D2 receptor antagonist II (ED50 = 11.66 μmol/kg). Molecular simulation study including fitting to dopamine D2 receptor antagonists 3D-pharmacophore model using Discovery Studio 2.5 programs showed high-fit values. The experimental dopamine D2 receptor antagonistic activity of compounds 1a-t was consistent with the molecular modeling study.