Synthesis and in vitro evaluation of salvinorin A analogues:: Effect of configuration at C(2) and substitution at C(18)

被引：56

作者：

Beguin, Cecile

Richards, Michele R.

Li, Jian-Guo

Wang, Yulin

Xu, Wei

Liu-Chen, Lee-Yuan

Carlezon, William A., Jr.

Cohen, Bruce M.

机构：

[1] McLean Hosp, Mol Pharmacol Lab, Belmont, MA 02478 USA

[2] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA

[3] McLean Hosp, Behav Genet Lab, Belmont, MA 02478 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 17期

关键词：

salvinorin; kappa-opioid receptor; structure-activity relationship; agonist; mood;

D O I：

10.1016/j.bmcl.2006.05.093

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

kappa-opioid receptor ligands have raised interest for their apparent effects on mood. The potent and selective kappa-agonist salvinorin A has short-lasting (15 min) depressive-like effects in rats in behavioral models used to study mood disorders. Two series of salvinorin derivatives modified at C(2) and C(18), respectively, were synthesized and their kappa-opioid receptor affinities, potencies, and efficacies were evaluated using in vitro receptor binding and biochemical functional assays. Modification at C(2) yielded potent kappa-agonists that are predicted to have improved metabolic stability (14a, 15a) or increased water solubility (10b). Our preliminary SAR study at C(18) suggested that this part of the molecule interacts with a tight lipophilic pocket of the K-receptor. (c) 2006 Elsevier Ltd. All rights reserved.

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收藏

页码：4679 / 4685

页数：7

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