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

This animal study (n=12) synthesized several different furan-substituted salvinorin A analogs and identified three potent variants which reduced drug-induced reinstatement of cocaine-seeking behavior, without producing the sedation observed with other κ-opioid agonists.

Abstract

“Introduction: 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.

Methods: Herein we report the synthesis of several salvinorin A derivatives with modified furan rings.

Results: 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.

Discussion: 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.”

Authors: Andrew P. Riley, Chad E. Groer, David Young, Amy W. Ewald, Bronwyn M. Kivell & Thomas E. Prisinzano

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