Modified Akuamma Alkaloids with Increased Potency at the Mu-opioid Receptor

Abstract

Akuammine (1) and pseudo-akuammigine (2) are indole alkaloids found in the seeds of the akuamma tree (Picralima nitida) that are used as a traditional treatment for pain in West Africa. Both alkaloids are agonists of the mu-opioid receptor (µOR); however, they produce minimal effects in animal models of antinociception, likely due to their modest potency. To further probe the interactions of 1 and 2 at the opioid receptors, we have prepared a collection of semi-synthetic derivatives with modifications to the C10, C11, C16, and N1 positions of the indole core. Evaluation of this collection at the µOR and kappa opioid receptor (κOR) revealed structural-activity relationship trends and derivatives with improved potency at the µOR. Most notably, the introduction of a phenethyl moiety to the N1 of 2 produces a 70-fold increase in potency and a 7-fold increase in selectivity for the µOR. The in vitro potency of this compound was reflected in vivo in rodents, producing an ED50 = 77.6 mg/kg and 77.1 mg/kg in a tail-flick antinociception assay and a hot-plate assay, respectively. The improved potency of these analogs highlights the promise of exploring natural product scaffolds that can be used to probe the opioid receptors.