Year: 2018
Type: dissertation
Abstract: The dopamine transporter (DAT) is a membrane protein essential to dopamine homeostasis. Abnormal dopamine homeostasis is implicated in multiple conditions including the newly discovered dopamine transporter deficiency syndrome (DTDS). DTDS is an autosomal-recessive disorder caused by mutations that impair DAT maturation. Bupropion and ibogaine can rescue DTDS DAT mutants. We therefore examine the structure-activity relationships responsible, in hopes of discovering more efficacious and potent compounds. An SAR-based screen of bupropion and ibogaine analogs demonstrated necessity for a secondary amine and single halogen substitution on bupropion along with a flexible heterocyclic ring, chair-like substituent and hydroxyl substitution on ibogaine. Lead candidates noribogaine and PAL594 were able to rescue mature DAT. We also report that there is no link between DAT inhibition and chaperoning, suggesting that chaperoning is mediated allosterically. Future studies should aim to validate the presence of the putative DAT allosteric site, computer-assisted drug discovery and a mouse model.
Source: TSpace (University of Toronto)
Author: Charles Sutton
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3173836586