Synthesis, structure and quantitative structure-activity relationships of σ receptor ligands, 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines Original Research Article

A set of the title compounds having different substituents (R1, R2) on their phenyl groups was synthesized to find σ receptor binding affinity. Among the compounds, 2b (R1R2Cl) has the most potent σ1-binding activity, while 2a (R1R2H, SA4503) was most selective to σ1 over σ2 receptor. The crystal structures of 2a and 2b were shown, by X-ray crystallography, to be similar except for the one torsional angle of their propylene parts. Quantitative structure-activity relationship study suggested the affinity of the compounds to the σ1 receptor was dependent on the electronic feature, Swain-Luptonʹs R or Sπ that was derived by molecular orbital method, of R1 and R2.