Synthesis and Evaluation of Alkaloids to Probe Membrane Receptors - Predoctoral Supplement

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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, specifically alkaloids, 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 products and use them as pharmacological tools to study GPCRs and LGICs. This research employs contemporary organic chemistry strategies and cutting-edge techniques in receptor pharmacology to answer questions with important biomedical consequences. As such, research in the Riley lab is a fertile training ground for graduate students interested in pursuing careers in medicinal chemistry and the pharmaceutical sciences. In this administrative supplement to parent award R35GM147005, we are requesting additional funds to support the research training and career development of Ana Lopez-Hernandez. Ana’s research training is an integral component of the parent award related to the synthesis and evaluation of Aristotelia alkaloids that inhibit the nicotinic acetylcholine receptors (nAChRs), a family of LGICs. This research will focus on developing a streamlined platform to rapidly generate, evaluate, and design compounds based on the aristoquinoline scaffold with high selectivity for individual nAChR subtypes. To help Ana achieve her long-term career goal of obtaining a position at a biotechnology company in the drug discovery sector, we have included additional activities to encourage Ana’s professional development. Ana will be given opportunities to enhance her scientific communication skills, build her leadership abilities, and gain invaluable experience in the biotechnology industry. Together, the research training and career development plan, which has been crafted based on a tailored and evolving Individual Development Plan, will enable Ana to build on her strong scientific foundation and become a successful member of the biomedical workforce.