N-(omega-(Tetralin-1-yl)alkyl) derivatives of 3,3-dimethylpiperidine are highly potent and selective sigma1 or sigma2 ligands.

摘要

Several 3, 3-dimethyl-N-[omega-(tetrahydronaphthalen-1-yl)alkyl]piperidine derivatives and some related compounds were prepared. Their affinities and sigma-subtype selectivities were investigated by radioligand binding assays, labeling sigma1 receptors with [3H]-SKF 10047 and sigma2 receptors with [3H]-DTG. Many tested compounds bound sigma1 and/or sigma2 receptors with nanomolar or subnanomolar IC50 values. Compound (+)-22, (+)-3,3-dimethyl-1-[3-(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-propyl]piperidine, was the most potent (IC50 = 0.089 nM) and selective sigma1 ligand (1340-fold), showing a 10-fold enantioselectivity. Compounds 29 (3, 3-dimethyl-1-[4-(6-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-butyl]piperidine) and 31 (3, 3-dimethyl-1-[5-(1,2,3, 4-tetrahydronaphthalen-1-yl)-n-pentyl]piperidine) were highly potent (IC50 = 0.016 nM and IC50 = 0.008 nM, respectively) and highly selective sigma2 ligands (more than 100000-fold).