Structural analogues of 5-OMe-BPAT: Synthesis and interactions with dopamine D-2, D-3, and serotonin 5-HT1A receptors

Several structural analogues of 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propy lamino]tetralin (5-OMe-BPAT, 1), a representative of a series of 2-aminotet ralin-derived benzamides with po ten tial atypical antipsychotic properties , were synthesized and evaluated for their ability to bind to dopamine D-2A , D-3, and serotonin 5-HT1A receptors in vitro. The structure-affinity rela tionships revealed that the aromatic ring of the benzamide moiety of 1 cont ributes to the high affinities for all three receptor subtypes. Furthermore , 1 may interact with the dopamine D-2 and D-3 receptors through hydrogen b ond formation with its carbonyl group. Investigation of the role of the ami de hydrogen atom by amide N-alkylation was not conclusive, since conformati onal aspects may be responsible for the decreased dopaminergic affinities o f the N'-alkylated analogues of 1. The effects of the amide modifications o n the serotonin 5-HT1A receptor affinity were less pronounced, suggesting t hat the benzamidoethyl side-chain of 1 as a whole enhances the affinity for this receptor subtype probably through hydrophobic interactions with an ac cessory binding site. The structural requirements for the substituents at t he basic nitrogen atom supported the hypothesis that the 2-aminotetralin mo ieties of the 2-aminotetralin-derived substituted benzamides may share the same binding sites as the 2-(N, N-di-n-propylamino)tetralins. (C) 1999 Else vier Science Ltd. All rights reserved.