Isolation and Synthetic Derivatisation of Indole Alkaloids as Probes for the Kappa Opioid Receptor

The evaluation of natural products has been crucial to the development of new therapeutics in terms of discovering drug candidates and developing molecular probes to understand their biological targets. Indole alkaloids, in particular, have found favour as privileged scaffolds for drug discovery. An interest in central nervous system (CNS) targets for pain and substance abuse, drew attention to two species from West African traditional medicine – Picralima nitida and Voacanga africana. P. nitida, commonly known as akuamma, has been used for centuries to treat various ailments including pain and fever. The analgesic properties have been attributed to indole alkaloids contained in the seeds. One of these alkaloids, akuammicine, is an agonist with significant affinity for the kappa opioid receptor (KOR) – an opioid receptor with a pharmacological profile void of the adverse effects associated with the mu opioid receptor. Leveraging a robust isolation method to access akuammicine, synthesis and evaluation of analogues revealed C10 derivatives with remarkable increases in affinity and potency, while maintaining KOR selectivity. Use of these analogues as in vitro and in vivo probes will yield greater understanding of the signalling and behavioural effects of the akuammicine scaffold at the KOR. The chemical composition of V. africana bears overwhelming similarity to Tabernanthe iboga – the main source of the indole alkaloid ibogaine – which has been anecdotally used as a long-lasting treatment for stimulant abuse. While the ability to study ibogaine is limited due to its classification as a Schedule I substance, the close resemblance of voacangine, the major alkaloid V. africana, may provide a plausible substitute for investigating ibogaine’s pharmacology, which includes KOR agonist activity. Synthetic conversion of voacangine into known voacangine and ibogaine metabolites yielded compounds that will be screened against a panel of >45 CNS receptors to deliver a comprehensive profile of their pharmacological activity. Altogether, these projects facilitate greater mechanistic understanding of P. nitida and V. africana metabolites, with the potential to develop novel analgesics with an improved safety profile and new substance abuse cessation treatments.