Interaction of Cocaine Analogue RTI82 With the Dopamine Transporter

L. K. Henry, J. D. Foster, John R. Lever, R. A. Vaughan

Research output: Chapter in Book/Report/Conference proceedingChapter


One of the major targets for cocaine in the central nervous system is the dopamine transporter (DAT), which clears dopamine from the extraneuronal space. Cocaine binds to DAT and inhibits reuptake, causing transmitter overflow and stimulation of downstream pathways that lead to euphoria and addiction. No pharmacological treatment for cocaine abuse currently exists, due in part to our dearth of knowledge regarding transporter structure and inhibitor binding mechanisms. To elucidate how cocaine interacts with DAT we utilized a synergistic approach involving irreversible labeling with the cocaine analogue 3β-(. p-chlorophenyl)tropane-2β-carboxylic acid, 4'-azido-3'-iodophenylethyl ester (RTI82), computational modeling of ligand poses, and ligand protection analyses. Our results directly demonstrate RTI82 binding in a site and orientation that is consistent with many biochemical findings, and indicate specific mechanisms of transport inhibition. These findings have major relevance for the molecular basis of cocaine actions, and the approaches developed will be useful for examination of structurally and mechanistically distinct categories of uptake blockers.

Original languageEnglish (US)
Title of host publicationThe Neuroscience of Cocaine
Subtitle of host publicationMechanisms and Treatment
PublisherElsevier Inc.
Number of pages9
ISBN (Electronic)9780128037928
ISBN (Print)9780128037508
StatePublished - May 16 2017
Externally publishedYes


  • Computational docking
  • Homology modeling
  • Molecular dynamics
  • Peptide mapping
  • Photoaffinity labeling
  • Substituted cysteine accessibility method

ASJC Scopus subject areas

  • General Psychology


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