2-aminotetralin-derived substituted benzamides with mixed dopamine D-2, D-3, 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 t he pharmacological concept of mixed dopamine D-2 receptor antagonism and se rotonin S-HT1A receptor agonism, was designed by combining the structural f eatures of the 2-(N,N-di-n-propylamino)tetralins (DPATs) and the 2-pyrrolid inylmethyl-derived substituted benzamides ina structural hybrid. Thus, a se ries of 35 differently substituted 2-aminotetralin-derived substituted benz amides was synthesized and the compounds were evaluated for their ability t o 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 recept ors in vitro. The lead compound of the series, 5-methoxy-2-[N-(2-benzamidoe thyl)-N-n-propylamino]tetralin (12a), displayed high affinities for the dop amine D-2A receptor (K-i = 3.2 nM), the dopamine D-3 receptor (K-i = 0.58 n M) 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 moie ties of the compounds occupy the same binding sites as the DPATs in all thr ee receptor subtypes. The benzamidoethyl side chain enhances the affinities of the compounds for an three receptor subtypes, presumably by occupying a n accessory binding site. For the dopamine D-2 and D-3 receptors, this acce ssory binding site may be identical to the binding site of the 2-pyrrolidin ylmethyl-derived substituted benzamides. (C) 1998 Elsevier Science Ltd. All rights reserved.