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


Akuammine (1) and pseudo-akuammigine (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 semi-synthetic 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 OR. 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.

Version notes

In addition to clarification of the text, additional data regarding the functional activity of compound 33 at the kappa and delta opioid receptors is now included. Additionally, we have demonstrated the in vivo activity of compound 33 is reversible by pretreating with the opioid receptor antagonist naloxone. We thank the reviewers and editors of this paper for their valuable feedback that has improved the content of this manuscript.


Supplementary material

Supporting Information
The following files are available free of charge. Additional supplementary figures (Figures S1-2) HPLC Chromatograph of compound 33. 1H NMR and 13C NMR spectra for compounds 7-33.