Synthesis and structure-activity relationships of N-(3-phenylpropyl)-N'-benzylpiperazines: Potent ligands for sigma1 and sigma2 receptors

Ten N-(3-phenylpropyl)-N'-benzylpiperazines having different substituents on the benzyl moiety were synthesized and evaluated for sigma(1) and sigma(2) receptor binding. The sigma(1) affinities were 0.37-2.80nM, sigma(2) affinities were 1.03-34.3nM, and selectivities, as sigma(2)/sigma(1) affinity ratios, ranged from 1.4 to 52. Three compounds tested in a phenytoin shift binding assay profiled as probable sigma(1) antagonists. Quantitative structure-activity relationships depended on pi(x), MR or E(s) and Hammett sigma values. The hydrophobicity term is negative for sigma(1) binding but positive for sigma(2) binding, indicating a major difference between the pharmacophores.