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 [3H] dopamine (DA) uptake and [3H]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.
|Number of pages||9|
|State||Published - Sep 1 2012|
Bibliographical noteFunding Information:
Support for this research was provided to AHN, OMO, JC, TK, MM, JLK, and GT by the National Institute on Drug Abuse Intramural Research Program. CJL is supported by the Lundbeck Foundation and the Danish Council for Independent Research Sapere Aude programme.
- Abuse liability
- dopamine transporter
ASJC Scopus subject areas
- Biological Psychiatry