1‐Cinnamyl‐4‐(2‐methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D₂) and Serotonin (5‐HT_1A) Receptors

Abstract

Clinical properties of atypical antipsychotics are based on their interaction with D(2) dopamine receptor and serotonin 5-HT(1A) and 5-HT(2A) receptors. As a part of our research program on new antipsychotics, we synthesized various derivatives of 1-cinnamyl-4-(2-methoxyphenyl)piperazines, and evaluated their affinities for D(2), 5-HT(1A), 5-HT(2A), and adrenergic (alpha(1)) receptors using radioligand-binding assays. In addition, we performed docking analysis using models for the D(2) and 5-HT(1A) receptors. All compounds exhibited low to moderate affinity to 5-HT(1A) and 5-HT(2A) receptors, high affinity to the D(2 )receptor and large variability in affinities for the alpha(1) receptor. Docking analysis indicated that the binding to D(2) and 5-HT(1A) receptors is based on (i) interaction between protonated N1 of the piperazine ring and various aspartate residues, (ii) hydrogen bonds between various moieties of the ligand and the residues of threonine, serine, histidine or tryptophane, and (iii) edge-to-face interactions of the aromatic ring of the arylpiperazine moiety with phenylalanine or tyrosine residues. Docking data for the D(2) receptor can account for the binding properties obtained in binding assays, suggesting that the model is reliable and robust. However, docking data for the 5-HT(1A) receptor cannot account for actual binding properties, suggesting that further refinement of the model is required.

New Arylpiperazines with Flexible versus Partly Constrained Linker as Serotonin 5‐HT1A/5‐HT7 Receptor Ligands

“…Long‐chain arylpiperazines (LCAP) are one of the commonly studied classes of bioactive compounds due to their large spectrum of potential therapeutic applications 1–10. Among them, a prominent place is occupied by pharmacological effects caused by interactions with different subtypes of serotonin receptors, which are known to be involved in the etiology of various mental diseases 1, 10.…”

Molecular Modeling of 5HT2A Receptor – Arylpiperazine Ligands Interactions

“…Ligand set 1 (compounds 1–7 ) : in case of ligands 1 and 6 , interactions between the tail part and the binding pocket are aromatic, most probably edge‐to‐face (ETF) and/or hydrophobic in nature (Figure ). Receptor amino acid residues Trp 336, Phe 339, and Tyr 370 can form ETF interactions, while Leu 123 and Val 366 will contribute to hydrophobic interactions.…”

N‐{[2‐(4‐Phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides with Dopamine D2 and 5‐Hydroxytryptamine 5HT1A Activity: Synthesis, Testing, and Molecular Modeling

“…N‐ Arylpiperazines are example of the so‐called “privileged structures” that are present in numerous high‐affinity ligands for different G‐protein coupled receptors . They can be agonists, partial agonists, or full agonists in D 2 , 5‐HT 1A , 5‐HT 2A , 5‐HT 7 , α1‐, and β1‐adrenergic receptor systems . It is rather difficult to predict binding and functional properties of N ‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides on different receptor systems solely on the basis of literature data.…”