Chiral, nonracemic (piperazin-2-yl)methanol derivatives with σ-receptor affinity

Abstract

Starting with the proteinogenic amino acid ( S)-serine a series of chiral nonracemic (piperazin-2-yl)methanols 3 with various N-4 substituents is described. The key step in the synthesis of 3 is the reaction of the chloroacetamide 5 with various primary amines to yield the diastereomeric bicyclic piperazinediones cis- 6 and trans- 6. The scope and limitation of this transformation is thoroughly investigated. The σ 1- and σ 2-receptor affinities of the piperazines 3 are determined in receptor binding studies with guinea pig brain and rat liver membrane preparations using [ 3H]-labeled (+)-pentazocine and ditolylguanidine, respectively. It was found, that an additional phenyl residue in the N-4 substituent is favorable to high σ 1-receptor affinity. In this series the p-methoxybenzyl substituted piperazine 3d reveals the highest σ 1-receptor affinity ( K i=12.4 nM) with selectivity toward σ 2-, NMDA-, κ-opioid, and μ-opioid receptors.