N-[ω-(tetralin-1-yl)alkyl] derivatives of 3,3-dimethylpiperidine are highly potent and selective σ1 or σ2 ligands

Several 3,3-dimethyl-N-[ω-(tetrahydronaphthalen-1-yl)alkyl]piperidine derivatives and some related compounds were prepared. Their affinities and σ-subtype selectivities were investigated by radioligand binding assays, labeling σ1 receptors with [3H]-SKF 10047 and σ2 receptors with [3H]-DTG. Many tested compounds bound σ1 and/or σ2 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 σ1 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 σ2 ligands (more than 100 000-fold).