Synthesis and Evaluation of the Aristotelia Alkaloids at the α3β4 Nicotinic Acetylcholine Receptor

Substance use disorders remain a major public health concern in the United States, affecting over 48 million individuals in 2024. Yet, while nearly a third of all overdose deaths in the US have been linked to stimulants like cocaine, there are currently no FDA-approved treatments to aid those dependent on stimulants. Of the many therapeutic targets and strategies that have been explored to develop a treatment for stimulant use disorders, the α3β4 nicotinic acetylcholine receptor (nAChR), a key modulator of the brain’s reward pathway, has proven promising. Antagonists for the α3β4 nAChR reduce drug-seeking behavior and withdrawal symptoms in rodent models, but a lack of selective ligands has limited further study. The solution may be found in the natural product aristoquinoline (ARQ), which is both moderately selective and potent at the α3β4 nAChR. This dissertation investigates the pharmacological utility of the α3β4 nAChR by developing two complementary assays to evaluate novel antagonists based on the ARQ scaffold: a calcium-based fluorescence assay and automated patch-clamp electrophysiology. Extensive subsequent analogue synthesis and assessment has identified compounds with enhanced potency and selectivity at the α3β4 nAChR relative to ARQ. Ongoing studies aim to define ARQ’s binding site and explore structurally related alkaloids for nAChR activity. From this work, we have expanded the toolbox of compounds and techniques to probe the α3β4 nAChR, supporting its potential as a target for the development of effective treatments for stimulant use disorders.

Author dc:creator

• Lisa E. Rusali (11172039)

• Chemistry
• Pharmaceutical

Statement dc:rights

• In Copyright
• Open Access after 2028-01-01

DOI dc:identifier

https://doi.org/10.25417/uic.31451806.v1

OAI identifier oai:identifier

oai:figshare.com:article/31451806