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

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.