title: 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.affiliation: Department of Chemistry and ‡Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Riley
authors.forename: Chad E
authors.initials: CE
authors.lastname: Groer
authors.forename: David
authors.initials: D
authors.lastname: Young
authors.forename: Amy W
authors.initials: AW
authors.lastname: Ewald
authors.forename: Bronwyn M
authors.initials: BM
authors.lastname: Kivell
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D045785:Diterpenes, Clerodane / Q000737:chemistry* / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry*; D006213:Hallucinogens / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D027544:Salvia / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D045785:Diterpenes, Clerodane; D005663:Furans; D006213:Hallucinogens; D017473:Receptors, Opioid, kappa; C090499:salvinorin A; C039281:furan