2-aminotetralin-derived substituted benzamides with mixed dopamine D2, D3, and serotonin 5-HT1A receptor binding properties:: A novel class of potential atypical antipsychotic agents

A new chemical class of potential atypical antypsychotic agents, based on the pharmacological concept of mixed dopamine D-2 receptor antagonism and serotonin S-HT1A receptor agonism, was designed by combining the structural features of the 2-(N,N-di-n-propylamino)tetralins (DPATs) and the 2-pyrrolidinylmethyl-derived substituted benzamides ina structural hybrid. Thus, a series of 35 differently substituted 2-aminotetralin-derived substituted benzamides was synthesized and the compounds were evaluated for their ability to compete for [H-3]-raclopride binding to cloned human dopamine D-2A and D-3 receptors, and for [H-3]-8-OH-DPAT binding to rat serotonin S-HT1A receptors in vitro. The lead compound of the series, 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (12a), displayed high affinities for the dopamine D-2A receptor (K-i = 3.2 nM), the dopamine D-3 receptor (K-i = 0.58 nM) as well as the serotonin 5-HT1A receptor (K-i = 0.82 nM). The structure-affinity relationships of the series suggest that the 2-amino-tetralin moieties of the compounds occupy the same binding sites as the DPATs in all three receptor subtypes. The benzamidoethyl side chain enhances the affinities of the compounds for an three receptor subtypes, presumably by occupying an accessory binding site. For the dopamine D-2 and D-3 receptors, this accessory binding site may be identical to the binding site of the 2-pyrrolidinylmethyl-derived substituted benzamides. (C) 1998 Elsevier Science Ltd. All rights reserved.