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

27 October 2022, Version 1
This content is an early or alternative research output and has not been peer-reviewed by Cambridge University Press at the time of posting.

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.

Keywords

opioid
pain
natural products
semi-synthesis
medicinal chemistry
biased agonism

Supplementary materials

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Supporting Information
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Supplementary Figures 1-3 HPLC of compound 33 1H and 13C NMR Spectra
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