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Is Cocaine Protonated When it Binds to the Dopamine Transporter?
Marie L Gram1, Julia M Warren1, Emilie L Madsen1
1Department of Chemistry, Faculty of Science, University of Copenhagen, Copenhagen DK-2100, Denmark.
JACS Au
|March 28, 2025
Summary
Cocaine binds to the human dopamine transporter (DAT) in its protonated form, resolving a long-standing controversy. This protonation explains the varying affinities of different cocaine analogues for DAT.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- The binding of cocaine to the human dopamine transporter (DAT) has been debated, particularly regarding its protonation state.
- Potent DAT inhibitors are typically strong amines, but some neutral cocaine analogues exhibit high affinity, creating conflicting structure-activity relationships.
Purpose of the Study:
- To investigate whether cocaine binds to the human dopamine transporter (DAT) in its protonated form.
- To elucidate the mechanism behind the varying affinities of cocaine analogues for DAT.
Main Methods:
- Utilized a fluorescent cocaine analogue with a lower pKa than cocaine.
- Determined the pKa of the aspartate residue in DAT implicated in cocaine binding.
Main Results:
- The fluorescent cocaine analogue was found to be protonated within the DAT binding site.
- The pKa of the critical aspartate residue in DAT was determined.
Conclusions:
- Cocaine is expected to bind to DAT in its protonated form.
- The determined pKa of the DAT aspartate residue explains the observed structure-activity data for cocaine analogues, resolving previous contradictions.
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