Year: 2025
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide There has been much controversy about whether the well-known alkaloid and tertiary amine base cocaine (p K a = 8.5) binds to the human dopamine transporter (DAT) in its protonated form. Most potent DAT inhibitors are also strong amines─yet there are some noteworthy examples where neutral cocaine analogues have high affinity, while the quaternary ammonium analog of cocaine, cocaine methiodide, is a comparatively poor inhibitor. In this paper, we show that a fluorescent cocaine analog, with a lower p K a than cocaine, becomes protonated in the DAT binding site and conclude that similar behavior must be expected from cocaine. By determining the p K a of the aspartate residue in DAT believed to interact with the amine of cocaine, we are able to explain the apparently contradictory structure–activity data of cocaine analogues.
Source: JACS Au
Institution: University of Copenhagen
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funder: Danmarks Frie Forskningsfond
Award: G1488601800
OpenAlex ID: W4407766569