The United States is simultaneously battling a pain crisis and the opioid epidemic. The combined need for treatment of both chronic pain and opioid addiction highlights the importance of developing analgesic medications which lack the dangerous side effects of current opioid therapies. Activation of the kappa opioid receptor (KOR) is known to produce an analgesic response without the adverse side effects of mu opioid receptor (MOR) drugs - namely, tolerance, physical dependence, and addiction. Following the trend of finding inspiration for novel analgesics in nature, we highlight the promising characteristics of akuammicine – an indole alkaloid from the akuamma tree – as a molecular probe for investigating the pharmacology of the KOR. Preliminary evaluation shows that akuammicine is a G-protein biased KOR agonist with submicromolar affinity (Ki = 89nm) and potency (EC50 = 240 nM). Having developed a robust method for isolating akuammicine from commercially available akuamma seeds, we present the semi-synthetic derivatisation of the akuammicine scaffold and primary evaluation of the acquired analogues. This work aims to ascertain the structure-activity relationships of akuammicine at the KOR and will aid in determining whether the KOR is a viable target for future analgesic drug discovery.

Investigating the structure-activity relationships of akuammicine – An alkaloid from Picralima nitida

ACS Fall 2021

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