title: 1-cinnamyl-4-(2-methoxyphenyl)piperazines: synthesis, binding properties, and docking to dopamine (D(2)) 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.
authors.affiliation: Centre for Chemistry, Institute for Chemistry, Technology and Metallurgy, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Penjisević
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sukalović
authors.forename: Deana
authors.initials: D
authors.lastname: Andrić
authors.forename: Sladjana
authors.initials: S
authors.lastname: Kostić-Rajacić
authors.forename: Vukić
authors.initials: V
authors.lastname: Soskić
authors.forename: Goran
authors.initials: G
authors.lastname: Roglić
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D017448:Receptors, Dopamine D2; D044263:Receptors, Serotonin, 5-HT1