Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 48, Issue 7, Pages 2548-2558Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm048999e
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We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT1AR affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT1AR ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions 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, K-i = 4.1 nM; alpha(1), Ki > 1000 nM) has been pharmacologically characterized as a 5-HT1AR agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.
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