Discovery of Potent Kappa Opioid Receptor Agonists Derived from Akuammicine

Akuammicine (1), an alkaloid isolated from Picralima nitida, is an agonist of the kappa opioid receptor (κOR). To establish structure–activity relationships (SARs) for this structurally unique κOR ligand, a collection of semisynthetic derivatives was synthesized. Evaluating these derivatives for their ability to activate the κOR and mu opioid receptor (μOR) revealed key SAR trends and identified derivatives with enhanced κOR potency. Most notably, substitutions to the C10 position of the aryl ring led to a > 200-fold improvement in κOR potency and nearly complete selectivity for the κOR. A selection of the most potent ligands was shown to possess differing abilities recruitment of β-Arrestin-2 to the κOR, indicating they have distinct signaling properties from each other and existing κOR ligands. The discovery of these κOR agonists underscores the potential of using natural products to identify new classes of potent and selective ligands and provides new tools to probe the κOR.