3,3 - 二甲基哌啶的N - [ω - （四氢萘 - 1 - 基）烷基]衍生物是高效且选择性的σ1或σ2配体。

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

作者信息

Berardi F, Santoro S, Perrone R, Tortorella V, Govoni S, Lucchi L

机构信息

Dipartimento Farmaco-Chimico, Università di Bari, via Orabona, 4, 70126 Bari, Italy, Istituto di Farmacologia, Università di Pavia, via Taramelli, 12, 27100 Pavia, Italy.

出版信息

J Med Chem. 1998 Oct 8;41(21):3940-7. doi: 10.1021/jm970692a.

DOI:10.1021/jm970692a

PMID:9767631

Abstract

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).

摘要

制备了几种3,3-二甲基-N-[ω-(四氢萘-1-基)烷基]哌啶衍生物及一些相关化合物。通过放射性配体结合试验研究了它们的亲和力和σ亚型选择性，用[³H]-SKF 10047标记σ1受体，用[³H]-DTG标记σ2受体。许多受试化合物以纳摩尔或亚纳摩尔的IC50值与σ1和/或σ2受体结合。化合物(+)-22，即(+)-3,3-二甲基-1-[3-(5-甲氧基-1,2,3,4-四氢萘-1-基)-正丙基]哌啶，是最有效的(IC50 = 0.089 nM)且具有选择性的σ1配体(选择性为1340倍)，表现出10倍的对映体选择性。化合物29(3,3-二甲基-1-[4-(6-甲氧基-1,2,3,4-四氢萘-1-基)-正丁基]哌啶)和31(3,3-二甲基-1-[5-(1,2,3,4-四氢萘-1-基)-正戊基]哌啶)是高效能的(IC50分别为0.016 nM和0.008 nM)且具有高选择性的σ2配体(选择性超过100000倍)。