2012
DOI: 10.1016/j.biopsych.2012.03.022
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R-Modafinil (Armodafinil): A Unique Dopamine Uptake Inhibitor and Potential Medication for Psychostimulant Abuse

Abstract: Background (±)-Modafinil has piqued interest as a treatment for ADHD and stimulant dependence. The R-enantiomer of modafinil may 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]DA uptake and [3H]WIN 35,428 binding in hDAT WT and mutants with altered conformational equilibria. Data were compared to cocaine and the atypical dopamine uptake inhibitor, JHW 007. R- and S-modafin… Show more

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Cited by 127 publications
(262 citation statements)
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References 62 publications
(99 reference statements)
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“…It has been suggested that the benztropines may bind distinct conformations of DAT and/or possess a slow rate of occupancy following administration, which may modulate the psychotropic effects of increased synaptic DA (11,37,105,106). Recently, modafinil and its R-enantiomer (armodafinil) have also been described as having distinctive interactions at DAT that might contribute to their nonaddictive and therapeutic profiles (96,(107)(108)(109). Thus, understanding cocaine binding in relation to compounds like these atypical DAT inhibitors could provide critical insights for developing medication strategies toward treating cocaine addiction.…”
Section: Discussionmentioning
confidence: 99%
“…It has been suggested that the benztropines may bind distinct conformations of DAT and/or possess a slow rate of occupancy following administration, which may modulate the psychotropic effects of increased synaptic DA (11,37,105,106). Recently, modafinil and its R-enantiomer (armodafinil) have also been described as having distinctive interactions at DAT that might contribute to their nonaddictive and therapeutic profiles (96,(107)(108)(109). Thus, understanding cocaine binding in relation to compounds like these atypical DAT inhibitors could provide critical insights for developing medication strategies toward treating cocaine addiction.…”
Section: Discussionmentioning
confidence: 99%
“…By disrupting a critical p-cation interaction needed for closure of the cytoplasmic gate, the Y335A mutation leads to a predominantly inward-facing transporter . In the Y335A mutant, binding of cocaine-like compounds was essentially ablated, but binding of benztropine, JHW007, and modafinil was less impacted, giving further credence to the idea that benztropine-like atypical inhibitors preferentially interact with the inwardfacing conformational state of the DAT (Loland et al, , 2012. Notably, compounds that exhibited a cocaine-like loss of binding at the Y335A mutant more readily substituted for cocaine in rat drug discrimination tests and were more potent locomotor stimulants in mice, demonstrating a correlation between conformational preference and cocaine-like behavioral effects.…”
Section: Atypical Uptake Inhibitors: Conformationspecific Binding Mecmentioning
confidence: 93%
“…Specifically, R-MOD has a B3-fold higher affinity for the DAT than S-MOD (Cao et al, 2010;Loland et al, 2012) and is more metabolically stable and longer acting (Dinges et al, 2006;Garnock-Jones et al, 2009). In addition, R-MOD appears to bind to the DAT more like atypical DA uptake inhibitors, exemplified by JHW 007, than like cocaine (Loland et al, 2012;OkunolaBakare et al, 2014). In this study, we found that R-MOD is more effective than S-MOD in inhibiting nicotine selfadministration in Long-Evans rats.…”
Section: Discussionmentioning
confidence: 99%
“…Given that ( ± )-MOD is a mixture of enantiomers and that R-MOD has higher affinity and potency at blocking the DAT (Cao et al, 2010;Loland et al, 2012) and an improved pharmacokinetic (PK) profile (Robertson and Hellriegel, 2003;Wong et al, 1999), we hypothesized that R-MOD may be more potent and effective than S-MOD or (±)-MOD in attenuating drug-taking and drug-seeking behavior. We tested this hypothesis in this study.…”
Section: Introductionmentioning
confidence: 99%