Authors:

Adam Makhlouf

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About Paper:

Psychostimulant Substance Use Disorder (pSUD) remains a significant unmet medical need, with no approved pharmacotherapies that directly treat pSUD. Recent studies from the CDC have shown that from 2021 to 2024, Stimulant-Involved Overdoses have led to more than 180,000 deaths in the United States. The a3B4 nicotinic acetylcholine receptor (nAChR) subtype emerged as a promising target due to its role in neural circuits that have been linked to addiction-relevant behavior and aversive/reinforcing signaling. Modulating this specific receptor subtype may provide a pathway-focused strategy to reduce relapse without broad receptor blockades. Our lab's work has already reported that aristoquinoline, a natural product found in Aristotelia chilensis, and its derivatives inhibit a3B4 nAChRs and reduce cocaine-seeking behavior in a rat reinstatement model. In this project, the chemical focus involves the development of aristoquinoline-based analogues containing biaryl substituents. The immediate goal is to synthesize methylated biaryl analogues of this structure, introducing steric bulk near the biaryl bond, thereby hindering rotation. The implementation of steric bulk forces aryl rings to adopt a more twisted, non-coplanar conformation. This design is expected to influence how the aromatic region occupies the a3B4 binding pocket, with the goal of improving subtype selectivity and potentially potency. After synthesis, the methylated biaryl analogues will be purified and structurally confirmed by column chromatography, nuclear magnetic resonance, and liquid chromatography mass-spectrometry. Purified compounds will be tested in mammalian cell lines expressing the a3B4 nAChR to assess potency and in 482 and a7 cell lines to assess selectivity. Results from this project will guide the next round of analogue design to further develop compounds that may be clinically relevant.

Source:

University of Illinois Chicago

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Co-authors:

Adam Makhlouf