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Characterizing novel allosteric modulators for human dopamine transporter
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Characterizing novel allosteric modulators for human dopamine transporter

Fuyu Yang
Master of Science (M.S.), Drexel University
May 2024
DOI:
https://doi.org/10.17918/00010445
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Abstract

Biology Allosteric regulation Cocaine use disorder Cocaine abuse Dopamine transporter
Cocaine use disorder (CUD) is an enduring and multifaceted health issue marked by uncontrollable cocaine use, despite harmful consequences. In the U.S., around 1.5 million people are affected by this disorder out of an estimated 2.2 million frequent users. Chronic cocaine misuse leads to numerous health problems, especially affecting the cardiovascular and neurological systems. Presently, there is no FDA- sanctioned drug treatment for CUD, underscoring the urgency to create effective therapies. Current treatment methods include psychosocial support and medication approaches using other psychostimulants such as amphetamines or GABAergic substances such as baclofen, though these have limited success and non-negligible side effects. We suggest a new treatment approach using dopamine transporter (DAT) allosteric modulators, which may mitigate cocaine's impact by altering structural conformations of DAT. This study aims to analyze four new analogs of two known allosteric modulators, KM822 and sydnocarb. Using structure/function studies including site-directed mutagenesis, dose response inhibition assays, and biotinylation protection studies, we've determined how each analog binds to DAT and its interaction with the allosteric site. Early animal trial results indicate that one of the compounds, FSM-3-174, diminishes cocaine-induced behavioral changes, showing promise as a potential CUD therapy.

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