R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse

Biol Psychiatry. 2012 Sep 1;72(5):405-13. doi: 10.1016/j.biopsych.2012.03.022. Epub 2012 Apr 25.


Background: (±)-Modafinil has piqued interest as a treatment for attention-deficit/hyperactivity disorder and stimulant dependence. The R-enantiomer of modafinil might have unique pharmacological properties that should be further investigated.

Methods: (±)-Modafinil and its R-(-)- and S-(+)-enantiomers were synthesized and tested for inhibition of [(3)H] dopamine (DA) uptake and [(3)H]WIN 35428 binding in human dopamine transporter (DAT) wild-type and mutants with altered conformational equilibria. Data were compared with cocaine and the atypical DA uptake inhibitor, JHW 007. R- and S-modafinil were also evaluated in microdialysis studies in the mouse nucleus accumbens shell and in a cocaine discrimination procedure.

Results: (±)-, R-, and S-modafinil bind to the DAT and inhibit DA uptake less potently than cocaine, with R-modafinil having approximately threefold higher affinity than its S-enantiomer. Molecular docking studies revealed subtle differences in binding modes for the enantiomers. R-modafinil was significantly less potent in the DAT Y156F mutant compared with wild-type DAT, whereas S-modafinil was affected less. Studies with the Y335A DAT mutant showed that the R- and S-enantiomers tolerated the inward-facing conformation better than cocaine, which was further supported by [2-(trimethylammonium)ethyl]-methanethiosulfonate reactivity on the DAT E2C I159C. Microdialysis studies demonstrated that both R- and S-modafinil produced increases in extracellular DA concentrations in the nucleus accumbens shell less efficaciously than cocaine and with a longer duration of action. Both enantiomers fully substituted in mice trained to discriminate cocaine from saline.

Conclusions: R-modafinil displays an in vitro profile different from cocaine. Future trials with R-modafinil as a substitute therapy with the potential benefit of cognitive enhancement for psychostimulant addiction are warranted.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / metabolism
  • Benzhydryl Compounds / pharmacokinetics*
  • Benzhydryl Compounds / therapeutic use
  • Central Nervous System Stimulants / metabolism
  • Central Nervous System Stimulants / pharmacokinetics*
  • Cocaine / metabolism
  • Cocaine / pharmacokinetics*
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopamine Uptake Inhibitors / metabolism
  • Dopamine Uptake Inhibitors / pharmacokinetics*
  • Dopamine Uptake Inhibitors / therapeutic use
  • Humans
  • Male
  • Mice
  • Microdialysis
  • Modafinil
  • Nucleus Accumbens / metabolism
  • Protein Binding
  • Substance-Related Disorders / drug therapy
  • Substance-Related Disorders / metabolism


  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Cocaine
  • Modafinil
  • Dopamine