Synthesis and Structure-Activity Relationships of a New Model of Arylpiperazines. 8. super(1) Computational Simulation of Ligand-Receptor Interaction of 5-HT sub(1A)R Agonists with Selectivity over alpha sub(1)-Adrenoceptors

We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT sub(1A)R affinity and selectivity over alpha sub(1)-adrenoceptors. The new selective 5-HT sub(1A)R 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-HT sub(1A), K sub(i) = 4.1 nM; alpha sub(1), K sub(i) > 1000 nM) has been pharmacologically characterized as a 5-HT sub(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp super(3.32) in TMH 3, Thr super(5.39) and Ser super(5.42) in TMH 5, and Tip super(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp super(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.