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

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

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

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.

Original languageEnglish
Pages (from-to)10464-10475
Number of pages12
JournalJournal of Medicinal Chemistry
Volume57
Issue number24
DOIs
StatePublished - Dec 26 2014

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues'. Together they form a unique fingerprint.

Cite this