Synthesis and structure–activity relationships of N-(3-phenylpropyl)- N′-benzylpiperazines: Potent ligands for σ1 and σ2 receptors

Abstract

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