| Abstract
| - We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT1ARaffinity and selectivity over α1-adrenoceptors. The new selective 5-HT1AR ligands contain ahydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separatedby one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists ofdifferent benzofused rings mimicking the favorable voluminous substituents at ortho and metapositions predicted by 3D-QSAR analysis in the previously reported series I. In particular,(S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9,CSP-2503] (5-HT1A, Ki = 4.1 nM; α1, Ki> 1000 nM) has been pharmacologically characterizedas a 5-HT1AR agonist at somatodendritic and postsynaptic sites, endowed with anxiolyticproperties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp3.32 in TMH 3, Thr5.39and Ser5.42 in TMH 5, and Trp6.48 in TMH 6. We propose that agonists modify, by means of anexplicit hydrogen bond, the conformation of Trp6.48 from pointing toward TMH 7, in the inactivegauche+ conformation, to pointing toward the ligand binding site, in the active transconformation.
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