Synthesis and Evaluation of Alkaloids to Probe Membrane Receptors

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ABSTRACT The discovery of new small molecules that perturb the function of membrane receptors, like G-protein coupled receptors (GPCRs) and ligand-gated ion channels (LGIC), remains critically important to the study and improvement of human health. Natural products are particularly well-suited for this task, as their structural complexity and unique mechanism of action make them superior chemical probes and excellent starting points for drug discovery. The Riley lab is focused on developing step-economic synthetic routes and robust isolation protocols to access these complex natural product scaffolds. Through modular total syntheses, semi-synthetic methods, and contemporary receptor assays, we transform natural products into highly potent and selective tools for studying membrane receptors. This application describes an overview of our work and future directions in applying these strategies to investigate the nicotinic acetylcholine receptors (nAChRs) and the kappa opioid receptor (κOR) as representative LGIC and GPCR, respectively. The first research area builds upon our work that recently identified members of the Aristotelia alkaloid family as potent inhibitors of the nAChRs, a major class of LGICs, with an unusual yet desirable subtype-selectivity. During this award, we will develop streamlined synthetic chemistry to access the entire class of Aristotelia alkaloids and generate large libraries of their derivatives. By coupling these synthetic chemistry efforts with an expanded ability to screen for activity against an array of nAChR subtypes and other membrane receptors, this work will deliver new chemical tools to probe the biological function of specific nAChR subtypes. In the second research area, we will explore a novel class of κOR agonists derived from the indole alkaloid akuammicine that were recently discovered in our laboratory. Our initial studies identified these akuammicine derivatives are potent biased agonist that preferentially activate the G-protein signaling pathway. Leveraging isolation protocols that provide synthetically useful quantities of complex alkaloids directly from their natural sources, we will employ late-state diversification techniques to rapidly generate novel derivatives that probe ligand-receptor interactions within the κOR and monitor their ability to initiate opioid signaling cascades. We expect the results from this research will reach beyond the nAChR and κOR and can be applied to other therapeutically relevant LGICs and GPCRs, thereby having a significant impact on drug discovery by revealing new directions to rationally design ligands for these important membrane receptors.