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ID: ALA5247645
Journal: J Med Chem
Title: Modified Akuamma Alkaloids with Increased Potency at the Mu-opioid Receptor.
Authors: Hennessy MR, Gutridge AM, French AR, Rhoda ES, Meqbil YJ, Gill M, Kashyap Y, Appourchaux K, Paul B, Wang ZJ, van Rijn RM, Riley AP.
Abstract: 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.
CiteXplore: 36827198