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

TY - JOUR

T1 - R-modafinil (armodafinil)

T2 - a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse

AU - Loland, Claus J

AU - Mereu, Maddalena

AU - Okunola, Oluyomi M

AU - Cao, Jianjing

AU - Prisinzano, Thomas E

AU - Mazier, Sonia

AU - Kopajtic, Theresa

AU - Shi, Lei

AU - Katz, Jonathan L

AU - Tanda, Gianluigi

AU - Newman, Amy Hauck

N1 - Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PY - 2012/9/1

Y1 - 2012/9/1

N2 - 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.

AB - 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.

KW - Animals

KW - Benzhydryl Compounds

KW - Central Nervous System Stimulants

KW - Cocaine

KW - Dopamine

KW - Dopamine Plasma Membrane Transport Proteins

KW - Dopamine Uptake Inhibitors

KW - Humans

KW - Male

KW - Mice

KW - Microdialysis

KW - Nucleus Accumbens

KW - Protein Binding

KW - Substance-Related Disorders

U2 - 10.1016/j.biopsych.2012.03.022

DO - 10.1016/j.biopsych.2012.03.022

M3 - Journal article

C2 - 22537794

SN - 0006-3223

VL - 72

SP - 405

EP - 413

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 5

ER -