Persistent binding at dopamine transporters determines sustained psychostimulant effects

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  • Marco Niello
  • Spyridon Sideromenos
  • Ralph Gradisch
  • Ronan O'Shea
  • Jakob Schwazer
  • Julian Maier
  • Nina Kastner
  • Walter Sandtner
  • Kathrin Jäntsch
  • Carl R. Lupica
  • Alexander F. Hoffman
  • Gert Lubec
  • Løland, Claus Juul
  • Thomas Stockner
  • Daniela D. Pollak
  • Michael H. Baumann
  • Harald H. Sitte

Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.

Original languageEnglish
Article numbere2114204120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
Number of pages11
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2023 the Author(s).

    Research areas

  • cathinones, dopamine transporter, drug-binding kinetics, new psychoactive substances, psychostimulants

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