Synthesis, Pharmacological Evaluation, and σ₁ Receptor Interaction Analysis of Hydroxyethyl Substituted Piperazines

Starting from (<i>S</i>)- or (<i>R</i>)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. σ receptor affinity was recorded using receptor material from both animal and human origin. σ₁ affinities determined with guinea pig brain and human RPMI 8226 tumor cell lines differed slightly but showed the same tendency. (<i>S</i>)-2-[4-(Cyclohexylmethyl)-1-(naphthalene-2-ylmethyl)­piperazin-2-yl]­ethanol (<b>7c</b>) revealed the highest affinity at human σ₁ receptors (<i>K</i>_i = 6.8 nM). The potent σ₁ receptor ligand <b>7c</b> was able to inhibit selectively the growth of three human tumor cell lines with IC₅₀ values in the low micromolar range. The reduced growth of the RPMI-8226 cell line was caused by apoptosis. The interaction of <b>7c</b> with the σ₁ receptor was analyzed in detail using the 3D homology model of the σ₁ receptor. The calculated free binding energies of all hydroxyethylpiperazines nicely correlate with their recorded affinities toward the human σ₁ receptor