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.

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability

“…Both compounds were tested for opioid activity using a functional assay that measures forskolin-induced cAMP accumulation in CHO cells stably expressing either MORs, KORs, or δ-opioid receptors (DORs) (Table 1). 15 The epimerization of 2 at the C2 position (e.g. 4 ) resulted in a complete loss of activity at both MOR and KORs.…”

Salvinorina A: terpeno alucinógeno presente en Salvia divinorum Epling & Játiva

“…Además, actúa en el receptor Kappa opioide como agonista selectivo, que a su vez se encuentra unido a proteí-nas G, también conocidas como kop r . Estos receptores producen una analgesia periférica grande, aunque también pueden causar analgesia central pero con un efecto menor [6,17,[41][42][43][44].…”

An examination of the cardiac actions of PD117,302, a κ-opioid receptor agonist

“…Clinically, κ agonist drugs such as spiradoline (U-62,066E) produced analgesia; however, marked adverse effects including diuresis, sedation, dysphoria and hallucinations (Wadenberg, 2003) halted development. Despite such findings, synthesis and development of novel κ agonist drugs has continued Le Naour et al, 2014;Riley et al, 2014).…”