N-[omega-(Tetralin-1-yl)alkyl] derivatives of 3,3-dimethylpiperidine are highly potent and selective sigma1 or sigma2 ligands.
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).
Dipartimento Farmaco-Chimico, Università di Bari, via Orabona, 4, 70126 Bari, Italy, Istituto di Farmacologia, Università di Pavia, via Taramelli, 12, 27100 Pavia, Italy.
F
F
Berardi
S
S
Santoro
R
R
Perrone
V
V
Tortorella
S
S
Govoni
L
L
Lucchi
D000818:Animals; D001921:Brain / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D000097605:Sigma-1 Receptor
D010880:Piperidines; D017480:Receptors, sigma; D013764:Tetrahydronaphthalenes; D000097605:Sigma-1 Receptor; C115060:3,3-dimethyl-1-(3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl)piperidine; C115061:3,3-dimethyl-1-(4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-butyl)piperidine; C115062:3,3-dimethyl-1-(5-(1,2,3,4-tetrahydronaphthalen-1-yl)-n-pentyl)piperidine; C106107:sigma-2 receptor