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

被引:27
作者
Bedürftig, S
Wünsch, B
机构
[1] Univ Munster, Inst Pharmazeut & Med Chem, D-48149 Munster, Germany
[2] Univ Freiburg, Inst Pharmazeut, D-79104 Freiburg, Germany
关键词
bicyclic piperazinediones; (piperazin-2-yl)methanols; sigma(1)-receptor ligands; sigma(2)-receptor ligands; structure-affinity relationships;
D O I
10.1016/j.bmc.2004.03.059
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 traps-6. The scope and limitation of this transformation is thoroughly investigated. The sigma(1)- and sigma(2)-receptor affinities of the piperazines 3 are determined in receptor binding studies with guinea pig brain and rat liver membrane preparations using [H-3]-labeled (+)-pentazocine and ditolylguanidine, respectively. It was found, that an additional phenyl residue in the N-4 substituent is favorable to high sigma(1)-receptor affinity. In this series the p-methoxybenzyl substituted piperazine 3d reveals the highest sigma(1)-receptor affinity (K-i = 12.4 nM) with selectivity toward sigma(2)-, NMDA-, kappa-opioid, and mu-opioid receptors. (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3299 / 3311
页数:13
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