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

Akuammine
(1) and pseudoakuammigine (2) are indole
alkaloids found in the seeds of the akuamma tree (Picralima
nitida). Both alkaloids are weak agonists
of the mu opioid receptor (μOR); however, they produce minimal
effects in animal models of antinociception. To probe the interactions
of 1 and 2 at the opioid receptors, we have
prepared a collection of 22 semisynthetic derivatives. 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 resulted in
increased efficacy in the tail-flick and hot-plate assays of antinociception.
The improved potency of these derivatives highlights the promise of
exploring natural product scaffolds to probe the opioid receptors.