title: R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse.
abstract: 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.
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claus J
authors.initials: CJ
authors.lastname: Loland
authors.forename: Maddalena
authors.initials: M
authors.lastname: Mereu
authors.forename: Oluyomi M
authors.initials: OM
authors.lastname: Okunola
authors.forename: Jianjing
authors.initials: J
authors.lastname: Cao
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.forename: Sonia
authors.initials: S
authors.lastname: Mazier
authors.forename: Theresa
authors.initials: T
authors.lastname: Kopajtic
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000493:pharmacokinetics*; D003042:Cocaine / Q000378:metabolism / Q000493:pharmacokinetics*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D017551:Microdialysis; D000077408:Modafinil; D009714:Nucleus Accumbens / Q000378:metabolism; D011485:Protein Binding; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine; D000077408:Modafinil; D004298:Dopamine