R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse.
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.
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R-modafinil S-modafinil (+/-)-Modafinil cocaine [2-(trimethylammonium)ethyl]-methanethiosulfonate R-enantiomer of modafinil R- and S-modafinil DA cocaine cocaine R-modafinil cocaine R-modafinil (+/-)-Modafinil [(3)H] dopamine DA [(3)H]WIN 35428 dopamine cocaine DA JHW 007 R- and S-modafinil cocaine (+/-)-, R-, and S-modafinil DA cocaine R-modafinil R-modafinil armodafinil dopamine DAT Y156F DAT Y335A DAT DAT E2C I159C human dopamine transporter DAT DAT