Synthesis, Biological, and Computational Evaluation of Substituted 1-(2-Methoxyphenyl)-4-(1-phenethylpiperidin-4-yl)piperazines and 1-(2-Methoxyphenyl)-4-[(1-phenethylpiperidin-4-yl)methyl]piperazines as Dopaminergic Ligands.

Sixteen new 1-(2-methoxyphenyl)-4-(1-phenethylpiperidin-4-yl)piperazines and 1-(2-methoxyphenyl)-4-[(1-phenethylpiperidin-4-yl)methyl]piperazines were synthesized to be used as probes for mapping the dopamine D2 receptor (D2 DAR) arylpiperazine binding site. All compounds were evaluated for their affinity toward D2 DAR in an in vitro competitive displacement assay. The most active one was 1-(2-methoxyphenyl)-4-{[1-(3-nitrophenethyl)piperidin-4-yl]methyl}piperazine (25) with an affinity of Ki  = 54 nM. Docking analysis was conducted on all herein described compounds, whereas molecular dynamic simulation was performed on ligand 25 to establish its mode of interaction with D2 DAR. Two possible docking orientations are proposed; the one with a salt bridge between the piperidine moiety and Asp114 of D2 DAR is more stable.