Discovery of Potent Kappa Opioid Receptor Agonists Derived from Akuammicine

Akuammicine (1), an indole alkaloid isolated from the seeds of Picralima nitida, is a selective agonist of the kappa opioid receptor (κOR). To establish structure-activity relationships (SAR) for this structurally unique κOR ligand, a collection of 26 semisynthetic derivatives of 1 were 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 over other CNS receptor targets. Activation of the κOR by these analogues also results in the recruitment of β-Arrestin-2, indicating they are balanced agonists and have distinct signaling properties from other recently identified κOR agonists. The discovery of these κOR agonists underscores the potential of using natural products to identify new classes of highly potent and selective ligands and provides new pharmacology tools to probe the κOR.