1-Cinnamyl-4-(2-methoxyphenyl)piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D2) and Serotonin (5-HT1A) Receptors

• Published in: Archiv der Pharmazie (Weinheim) Vol. 340; no. 9; pp. 456 - 465
• Main Authors: Penjisevic, Jelena, Sukalovic, Vladimir, Andric, Deana, Kostic-Rajacic, Sladjana, Soskic, Vukic, Roglic, Goran
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.09.2007; WILEY‐VCH Verlag; Wiley
• Subjects: 5-HT2A receptor; Animals; Antipsychotic Agents - chemical synthesis; Antipsychotic Agents - chemistry; Antipsychotic Agents - metabolism; Binding Sites; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Dopamine D2 receptor; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Piperazines; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - metabolism; Receptors, Dopamine D2 - metabolism; Receptors, Serotonin, 5-HT1 - metabolism; Science & Technology; Serotonin 5-HT1A; Structure-Activity Relationship; dopamine D-2 receptor; serotonin 5-HT1A; 5-HT2A receptor; DESIGN; RECOGNITION; piperazines; PROTEIN-COUPLED RECEPTORS; ANTAGONISTS; AGONISTS
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.200700062

Clinical properties of atypical antipsychotics are based on their interaction with D2 dopamine receptor and serotonin 5‐HT1A and 5‐HT2A 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 D2, 5‐HT1A, 5‐HT2A, and adrenergic (α1) receptors using radioligand‐binding assays. In addition, we performed docking analysis using models for the D2 and 5‐HT1A receptors. All compounds exhibited low to moderate affinity to 5‐HT1A and 5‐HT2A receptors, high affinity to the D2 receptor and large variability in affinities for the α1 receptor. Docking analysis indicated that the binding to D2 and 5‐HT1A 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 D2 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‐HT1A receptor cannot account for actual binding properties, suggesting that further refinement of the model is required.