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

Abstract

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.

μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

“…The preparation of rat caudate nuclei synaptosomal membranes for D 2 DAR binding experiments was described in detail in previous publications. 17,18 Radioligand binding assay. The [ 3 H] spiperone binding assay was performed in 4 mM MgCl 2 , 1.5 mM CaCl 2 , 5 mM KCl, 120 mM NaCl, 25 mM Tris-HCl solution, pH 7.4, at a membrane protein concentration of 0.7 mg mL -1 at 37 °C for 10 min in a total volume of 0.4 mL of the incubation mixture.…”

Identification of Novel Dopamine D2 Receptor Ligands—A Combined In Silico/In Vitro Approach

“…This was shown in different studies investigating D 2 R agonists. Therefore, the combination of SB and LB virtual screening approaches is recommended to cover a broad chemical space of active compounds in screening campaigns [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”