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Flmodafinil
Wakefulness-promoting drug/Dopamine reuptake inhibitor From Wikipedia, the free encyclopedia
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Flmodafinil (developmental code names CRL-40,940, NLS-4, JBG01-41), also known as bisfluoromodafinil and lauflumide, is a wakefulness-promoting agent related to modafinil which has been developed for treatment of a variety of different medical conditions.[2][3][4] These include chronic fatigue syndrome, idiopathic hypersomnia, narcolepsy, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease.[3][4] Aside its development as a potential pharmaceutical drug, flmodafinil is sold online and used non-medically as a nootropic (cognitive enhancer).[5][6][7]
The drug has been found to act as a selective atypical dopamine reuptake inhibitor.[2][8][1][9] It produces wakefulness-promoting effects in animals.[2][8] Unlike modafinil, flmodafinil does not induce cytochrome P450 enzymes.[2] Chemically, flmodafinil is an enantiopure derivative of modafinil and is also known as bisfluoromodafinil (it is the (R)-bis(4-fluoro) phenyl ring-substituted derivative of modafinil).[2][8]
Flmodafinil was developed by NLS Pharma.[3] As of January 2024, it is in preclinical development for treatment of chronic fatigue syndrome.[3] No recent development has been reported for idiopathic hypersomnia and development has been discontinued for narcolepsy, ADHD, and Alzheimer's disease.[3]
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Pharmacology
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Pharmacodynamics
Flmodafinil is a selective dopamine reuptake inhibitor (DRI).[2][8][10] Its affinity (Ki) for the DAT is 4,090 nM.[10] At the serotonin transporter (SERT), its affinity (Ki) was 48,700 nM (12-fold lower than for the DAT), and it had negligible affinity for the sigma σ1 receptor (Ki > 100,000 nM).[10] The drug has been found to block the dopamine transporter (DAT) by 83%, to a greater extent than methylphenidate without unfavorable concomitant adrenergic effects.[8] The drug is an atypical DRI similarly to modafinil.[11][1][9]
The affinities for the DAT of flmodafinil's enantiomers and modafinil have also been studied.[1][10] The affinities (Ki) were 5,480 nM for armodafinil ((R)-modafinil), 2,970 nM for (S)-(+)-flmodafinil (JBG1-048), and 4,830 nM for (R)-(–)-flmodafinil (JBG1-049).[1][10] Their affinities for the SERT and σ1 receptor have also been reported.[10] Similarly to modafinil, (S)-(+)-flmodafinil and (R)-(–)-flmodafinil increase dopamine levels in the nucleus accumbens in animals.[1] They have been found to increase dopamine levels by up to 150 to 200% of baseline at the highest assessed dose.[1] These increases are much smaller than those elicited by amphetamine or cocaine.[1][12]
In a study comparing the wake-promoting effects of flmodafinil and modafinil, flmodafinil was found to maintain wakefulness over a significantly longer timeframe than modafinil.[8] While the administration of neither compound resulted in sleep rebound, flmodafinil perturbed sleep architecture to a lesser degree than modafinil.[8] This difference was characterised by an attenuated EEG power density within slow frequencies (<4 Hz) following flmodafinil treatment, though both compounds increased power density relative to placebo.[8]
In contrast to modafinil, flmodafinil is not an inducer of the cytochrome P450 CYP3A4 or CYP3A5 enzymes.[2]
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Chemistry
Flmodafinil is a racemic mixture of (S)-(+)- and (R)-(–)-enantiomers.[11][1] The (S)-(+) enantiomer has been referred to as JBG1-048 and the (R)-(–) enantiomer has been referred to as JBG1-049.[1]
Analogues of flmodafinil include modafinil, armodafinil ((R)-modafinil), esmodafinil ((S)-modafinil), adrafinil (CRL-40,028; N-hydroxymodafinil), fladrafinil (CRL-40,941; bisfluoroadrafinil), and CE-123, among others.
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History
Flmodafinil was patented in 2013, and preclinical research has been underway since December 2015.[3][4][13][14][15][16] It appears to have first been patented in the 1980s.[17][13]
Research
The pharmacokinetics of flmodafinil are being studied.[18]
References
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