N-[OMEGA-(TETRALIN-1-YL)ALKYL] DERIVATIVES OF 3,3-DIMETHYLPIPERIDINE ARE HIGHLY POTENT AND SELECTIVE SIGMA(1) OR SIGMA(2) LIGANDS

Several [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 sigma(1) receptors with [H-3]-SKF 10047 and sigma(2) recepto rs with [H-3]-DTG. Many tested compounds bound sigma(1) and/or sigma(2 ) receptors with nanomolar or subnanomolar IC50 values. Compound (+)-2 2, ,4-tetrahydronaphthalen-1-yl)-n-propyl]piperidine, was the most pot ent (IC50 = 0.089 nM) and selective sigma(1) ligand (1340-fold), showi ng a 10-fold enantioselectivity. Compounds 29 3,4-tetrahydronaphthalen -1-yl)-n-butyl]piperidine) and 31 ,4-tetrahydronaphthalen-1-yl)-n-pent yl]piperidine) were highly potent (IC50 = 0.016 nM and IC50 = 0.008 nM , respectively) and highly selective sigma(2) ligands (more than 100 0 00-fold).