Synthesis and biological evaluation of 2-alkyl-2-methoxymethyl-salvinorin ethers as selective κ-opioid receptor agonists

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Lee, David Y. W.¹  Deng, Gang¹  Ma, Zhongze¹  Xu, Wei^2,3  Yang, Lu¹  Liu, Jing¹  Dai, Ronghua¹  Liu-Chen, Lee-Yuan^2,3 

[1] Harvard Univ, McLean Hosp, Sch Med, Bioorgan & Nat Prod Lab, Belmont, MA 02478 USA

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

[3] Temple Univ, Sch Med, Ctr Substance Abuse Res, Philadelphia, PA 19140 USA

关键词: kappa-opioid;    Receptor;    Affinity;    Agonist;   

DOI  :  10.1016/j.bmcl.2015.06.092

来源: Elsevier

【 摘 要 】

The synthesis of a new series of C-2-alkyl-2-methoxymethyl-salvinorin ethers and their binding affinities at kappa-, mu-, and delta-opioid receptors are presented. We have developed a synthesis that enables installation of alkyl-substituents at C-2 while maintaining the integrity of the C-2 methoxymethyl ether and retaining kappa-opioid receptor binding activity. Among these new compounds, 2-methyl-2-methoxymethyl-salvinorin ether (9a) is a potent full agonist at the kappa receptor and shows comparable potency in K-i and EC50 with salvinorin A and U50488H. These C2-alkylated analogs have been identified as full kappa agonists. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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