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.

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Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands.