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

Introduction

Kappa-opioid receptors (KOR) and their endogenous ligands, the dynorphins, are widely expressed in the central nervous system and have been implicated in pain, drug abuse and mood disorders. Development of KOR-targeted therapeutics has been limited by adverse effects associated with many classical KOR ligands, including dysphoria, sedation and depression, and by pharmacokinetic issues with some antagonists. Earlier work has shown that structurally distinct ligands can produce different signalling outcomes at a single receptor (functional selectivity), suggesting that novel scaffolds might provide beneficial effects with fewer side effects. Riley and colleagues focused on salvinorin A, a neoclerodane diterpene natural product that is a potent, selective KOR agonist but is structurally unlike classical opioids and lacks a basic nitrogen. Although many positions on salvinorin A have been explored by semisynthetic modification, the role of the furan ring (C-15/C-16 positions) in KOR binding and activity remained under-investigated. This study set out to synthesize a series of furan-substituted salvinorin A analogues, characterise their KOR activity in a cellular functional assay, and test selected potent analogues in an animal model of cocaine relapse to determine whether small furan modifications could retain activity while avoiding sedation.