Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues.

Summary

Salvinorin A, a compound from Salvia divinorum, shows potential as a treatment for substance abuse due to its ability to activate κ-opioid receptors. New derivatives with modified furan rings were synthesized and tested, revealing that less bulky substitutions are more effective in binding to the receptor. The most potent derivative significantly reduced drug-seeking behavior in an animal model of drug relapse without causing sedation, unlike other κ-opioid agonists.

Study at a glance

Abstract

The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other κ-opioid agonists.