2-Aminotetralin-derived substituted benzamides with mixed dopamine D2, D3, and serotonin 5-HT(1A) receptor binding properties: A novel class of potential atypical antipsychotic agents

Article abstract of DOI:10.1016/S0968-0896(98)00167-9

A new chemical class of potential atypical antypsychotic agents, based on the pharmacological concept of mixed dopamine D₂ receptor antagonism and serotonin 5-HT(1A) 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 in a 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 [³H]-raclopride binding to cloned human dopamine D(2A) and D₃ receptors, and for [³H]-8-OH-DPAT binding to rat serotonin 5-HT(1A) 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)=3.2nM), the dopamine D₃ receptor (K(i)=0.58nM) as well as the serotonin 5-HT(1A) receptor (K(i)=0.82nM). The structure-affinity relationships of the series suggest that the 2-aminotetralin 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 all three receptor subtypes, presumably by occupying an accessory binding site. For the dopamine D₂ and D₃ receptors, this accessory binding site may be identical to the binding site of the 2-pyrrolidinylmethyl-derived substituted benzamides. Copyright (C) 1998 Elsevier Science Ltd.