Chiral, nonracemic (piperazin-2-yl)methanol derivatives with sigma-receptor affinity.
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 alpha1- and sigma2-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 sigma1-receptor affinity. In this series the p-methoxybenzyl substituted piperazine 3d reveals the highest sigma1-receptor affinity (Ki=12.4 nM) with selectivity toward sigma2-, NMDA-, kappa-opioid, and mu-opioid receptors.
Bedürftig
Stephan
S
Pharmazeutisches Institut der Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, D-79104 Freiburg i. Br., Germany.
Wünsch
Bernhard
B
D000818:Animals; D006168:Guinea Pigs; D008024:Ligands; D000432:Methanol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism*; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism
C495616:(piperazin-2-yl)methanol; D008024:Ligands; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D000077489:Piperazine; D000432:Methanol