Thesis
Pharmacological study of KM822 analogs: a novel class of dopamine transporter inhibitors
Master of Science (M.S.), Drexel University
Jun 2018
DOI:
https://doi.org/10.17918/D88Q2W
Abstract
The dopamine transporter (DAT) is a membrane protein that is responsible for the reuptake of dopamine back into the presynaptic neurons. DAT has been investigated intensively as a therapeutic target for substance abuse, depression, and attention deficit hyperactivity disorder. In the category of drugs of abuse, cocaine and other psychostimulants including amphetamine competitively inhibit all monoamine transporters, including dopamine transporter, norepinephrine transporter (NET) and serotonin transporter (SERT). By this mechanism, cocaine gives a sense of euphoria, and leads to dependency in the users. Chronic cocaine users have difficulty ceasing their cocaine abuse, and this leave cocaine addiction as a severe problem to the society. DAT has stood out to be a very promising target treating cocaine addiction. In a previous study, a region within the DAT has been found to modulate the transporter allosterically by comparing human dopamine transporter (hDAT) to a catecholamine transporter from Schistosoma mansoni. An allosteric site within hDAT was found based on the S. mansoni study using virtual screening, a small compound, called KM822, was identified. This compound was later shown to be binding at the predicted allosteric binding site in hDAT. Additionally, KM822 was shown to inhibit dopamine uptake and to inhibit cocaine binding to the transporter. Herein, we tested KM822 and KM822 analogs to investigate the structure-activity relationship between the transporter and these compounds. The overall goal of this project was to study the inhibitory properties of the KM822 class of compounds on dopamine uptake, as well as their effect on cocaine inhibition of DAT using cell-based functional assays. Also, we pursued to identify the structural characteristic that favors the interaction of these analogs with hDAT by conducting biotinylation assays. Future in vivo studies will be performed by colleagues to investigate the effect of these compounds on cocaine mediated behaviors in rodent models.
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Details
- Title
- Pharmacological study of KM822 analogs
- Creators
- Xiaonan Liu - DU
- Contributors
- Paul McGonigle (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xi, 77 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 8125; 991014632570804721