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

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.

• Authors: Andrew P Riley, Chad E Groer, David Young, Amy W Ewald, Bronwyn M Kivell, Thomas E Prisinzano
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 24 Pg. 10464-75 (Dec 26 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25426797 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Diterpenes, Clerodane
• Furans
• Hallucinogens
• Receptors, Opioid, kappa
• salvinorin A
• furan

Topics

• Animals
• CHO Cells
• Cricetulus
• Diterpenes, Clerodane (chemistry, pharmacology)
• Furans (chemistry)
• Hallucinogens (chemistry, pharmacology)
• Male
• Models, Molecular
• Molecular Structure
• Motor Activity (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid, kappa (agonists)
• Salvia (chemistry)
• Structure-Activity Relationship