Picralima nitida (akuamma) has been used for centuries in West African traditional medicine to treat multiple ailments including pain and fever. Akuammicine, an indole alkaloid isolated from the seeds of the akuamma tree, is an agonist at the kappa opioid receptor (KOR). KOR agonists are capable of eliciting an analgesic response without the adverse side effects of conventional mu opioid receptor (MOR) agonists such as tolerance, addiction and respiratory depression. KOR compounds may therefore be a viable alternative to current opioid therapeutics. Preliminary evaluation indicates that akuammicine has submicromolar affinity (Ki = 89 nM) and potency (EC50 = 240 nM) at the KOR. Previously, our lab has developed a robust method for isolating akuammicine from commercially available akuamma seeds. Herein we present the late-stage derivatisation of akuammicine for the purpose of studying its structure-activity relationships at the KOR. We have discovered analogues which exhibit drastically increased affinity and potency at the receptor while maintaining selectivity for the KOR against &gt;45 CNS receptors and thus warrant further investigation.

Late-stage derivatisation of akuammicine for probing kappa opioid receptor activity

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