Flmodafinil Explained

Flmodafinil (developmental code names CRL-40,940, NLS-4), 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.[1] [2] These include chronic fatigue syndrome, idiopathic hypersomnia, narcolepsy, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease. Aside its development as a potential pharmaceutical drug, flmodafinil is sold online and used non-medically as a nootropic (cognitive enhancer).[3] [4] [5]

The drug has been found to act as a selective atypical dopamine reuptake inhibitor.[6] It produces wakefulness-promoting effects in animals. Unlike modafinil, flmodafinil does not induce cytochrome P450 enzymes. 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).

Flmodafinil was developed by NLS Pharma. As of January 2024, it is in preclinical development for treatment of chronic fatigue syndrome. No recent development has been reported for idiopathic hypersomnia and development has been discontinued for narcolepsy, ADHD, and Alzheimer's disease.

Pharmacology

Pharmacodynamics

Flmodafinil is a selective dopamine reuptake inhibitor.[7] [8] It has been found to block the dopamine transporter by 83%, to a greater extent than methylphenidate without unfavorable concomitant adrenergic effects. The drug is an atypical dopamine reuptake inhibitor similarly to modafinil.

The affinities for the dopamine transporter of flmodafinil's enantiomers and modafinil have been studied. The affinities (Ki) were 5,480nM for armodafinil ((R)-modafinil), 2,970nM for (S)-(+)-flmodafinil (JBG1-048), and 4,830nM for (R)-(–)-flmodafinil (JBG1-049). Similarly to modafinil, (S)-(+)-flmodafinil and (R)-(–)-flmodafinil increase dopamine levels in the nucleus accumbens in animals. They have been found to increase dopamine levels by up to 150 to 200% of baseline at the highest assessed dose. These increases are much smaller than those elicited by amphetamine or cocaine.[9]

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. While the administration of neither compound resulted in sleep rebound, flmodafinil perturbed sleep architecture to a lesser degree than modafinil. This difference was characterised by an attenuated EEG power density within slow frequencies (<4Hz) following flmodafinil treatment, though both compounds increased power density relative to placebo.

In contrast to modafinil, flmodafinil is not an inducer of the cytochrome P450 CYP3A4 or CYP3A5 enzymes.

Chemistry

Flmodafinil is a racemic mixture of (S)-(+)- and (R)-(–)-enantiomers.[10] [11] The (S)-(+) enantiomer has been referred to as JBG1-048 and the (R)-(–) enantiomer has been referred to as JBG1-049.

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.

History

Flmodafinil was patented in 2013, and preclinical research has been underway since December 2015.[12] [13] [14] [15] It appears to have first been patented in the 1980s.[16]

Research

The pharmacokinetics of flmodafinil are being studied.[17]

Notes and References

  1. Web site: Lauflumide - NLS Pharmaceutics Ltd . AdisInsight . 28 January 2024 . 17 August 2024.
  2. Web site: Pipeline . monsolfoundation.ch . 30 September 2022 . 17 August 2024.
  3. Sousa A, Dinis-Oliveira RJ . Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects . Subst Abus . 41 . 2 . 155–173 . 2020 . 31951804 . 10.1080/08897077.2019.1700584 . Modafinil is a highly researched compound, with many analogues created and studied (Figure 1); the wakefulness promoting agents CRL-40,490 and modafiendz are the fluoro and N-methyl analogs of modafinil and the CRL-40,491 is the fluoro analog of adrafinil.30,31 [...] Although the long-term effects in healthy individuals are unknown, modafinil is easily available online with limited information about the use of and potential harms related to the drug.20,209 Other possibilities available from online shops and other retail outlets include adrafinil, CRL-40,940, CRL40,941 and modafiendz.30 Alternatively to online purchase, students also report to obtain stimulants from a pharmacy with or without prescription, from colleagues, friends or family, or from an herbalist.20.
  4. Schifano F, Catalani V, Sharif S, Napoletano F, Corkery JM, Arillotta D, Fergus S, Vento A, Guirguis A . Benefits and Harms of 'Smart Drugs' (Nootropics) in Healthy Individuals . Drugs . 82 . 6 . 633–647 . April 2022 . 35366192 . 10.1007/s40265-022-01701-7 . [Modafinil] is widely available for online purchase [105] and it is of interest that a range of modafinil derivatives are actively being discussed on web fora, including: adrafinil, fladrafinil, flmodafinil, and N-methyl-4,4′-difluoro-modafinil [8]. Finally, the modafinil R-enantiomer armodafinil, which is being used to improve wakefulness in patients with excessive sleepiness [106], is currently the subject of an anecdotal debate relating to its properties as a [cognitive enhancer] [107]..
  5. Dowling G, Kavanagh PV, Talbot B, O'Brien J, Hessman G, McLaughlin G, Twamley B, Brandt SD . Outsmarted by nootropics? An investigation into the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940 and CRL-40,941 in the GC injector: formation of 1,1,2,2-tetraphenylethane and its tetra fluoro analog . Drug Test Anal . 9 . 3 . 518–528 . March 2017 . 27928893 . 10.1002/dta.2142 .
  6. Zanettini C, Scaglione A, Keighron JD, Giancola JB, Lin SC, Newman AH, Tanda G . Pharmacological classification of centrally acting drugs using EEG in freely moving rats: an old tool to identify new atypical dopamine uptake inhibitors . Neuropharmacology . 161 . 107446 . December 2019 . 30481526 . 8369976 . 10.1016/j.neuropharm.2018.11.034 . The atypical DUI modafinil and its F-analog, JBG1-049, decreased the power of beta, but in contrast to cocaine, none of the other frequency bands, while JHW007 did not significantly alter the EEG spectrum. [...] Comparative analysis of the effects of test drugs on EEG indicates a potential atypical profile of JBG1-049 with similar potency and effectiveness to its parent compound modafinil. [...] In summary, quantitative analysis of EEG spectra revealed different neurosignatures of typical and atypical DUIs and of other central nervous system active drugs. These data suggest that evaluation of the EEG signal can be used to identify new DUIs, such as JBG 1-049, with potential atypical profiles in the early preclinical phase of drug development and can accelerate the discovery of possible treatments for psychostimulant use disorders..
  7. Konofal E . From past to future: 50 years of pharmacological interventions to treat narcolepsy . Pharmacol Biochem Behav . 241 . 173804 . August 2024 . 38852786 . 10.1016/j.pbb.2024.173804 . Among these advancements is lauflumide (NLS-4), a forward step from earlier substances initially envisioned by Lafon Laboratories yet not realized (Dowling et al., 2017). Developed by NLS Pharmaceutics AG, lauflumide represents a cutting-edge development as a selective dopamine reuptake inhibitor. It is an enantiomerically pure R-isomer, with an enantiomeric excess exceeding 95 %, of a bis(p-fluoro) phenyl ring-substituted derivative of modafinil, showcasing the innovative work of inventor Eric Konofal (USPTO Patent 2017, US9637447B2) (Konofal, 2017). Unlike modafinil, which induces hepatic enzyme activity with repeated doses, lauflumide does not act as an inducer of cytochrome P450 (CYP) enzymes, including CYP3A4/5. In mouse models, lauflumide has demonstrated potent wake-promoting effects without the risk of hypersomnia rebound (unpublished data). Moreover, the recovery sleep following lauflumide administration is marked by a reduced amount of NREM sleep and delta wave activity, indicating a decreased need for recovery sleep despite extended periods of wakefulness induced by the drug (Luca et al., 201).. free .
  8. Luca G, Bandarabadi M, Konofal E, Lecendreux M, Ferrié L, Figadère B, Tafti M . Lauflumide (NLS-4) Is a New Potent Wake-Promoting Compound . Front Neurosci . 12 . 519 . 2018 . 30158846 . 6104159 . 10.3389/fnins.2018.00519 . free . Preliminary findings suggest that NLS-4 is a selective dopamine reuptake inhibitor, blocking (83%) dopamine transporter (DAT), higher than methylphenidate and without deleterious effects on peripheral adrenergic systems involved in hypertension (Study 100014859 CEREP 20/03/14, unpublished data)..
  9. Ramsson ES, Howard CD, Covey DP, Garris PA . High doses of amphetamine augment, rather than disrupt, exocytotic dopamine release in the dorsal and ventral striatum of the anesthetized rat . J Neurochem . 119 . 6 . 1162–1172 . December 2011 . 21806614 . 3213283 . 10.1111/j.1471-4159.2011.07407.x .
  10. Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH . Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder . Curr Opin Pharmacol . 56 . 13–21 . February 2021 . 32927246 . 8247144 . 10.1016/j.coph.2020.07.007 . JBG1–048 and JBG1–049, two bis F-MOD enantiomers, administered intravenously, produced dose-dependent increases in DA efflux similar to, but longer lasting than those elicited by (R)-MOD [45] or MOD [42]..
  11. Keighron JD, Giancola JB, Shaffer RJ, DeMarco EM, Coggiano MA, Slack RD, Newman AH, Tanda G . Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats . Eur J Neurosci . 50 . 3 . 2045–2053 . August 2019 . 30402972 . 8294075 . 10.1111/ejn.14256 .
  12. Benzhydrylsulfinylacetamide derivatives . CA . 1199916 . Lafon L . Cephalon France SAS . 28 January 1986 . 28 January 1986 .
  13. Cao J, Prisinzano TE, Okunola OM, Kopajtic T, Shook M, Katz JL, Newman AH . Structure-Activity Relationships at the Monoamine Transporters for a Novel Series of Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) Analogues . ACS Medicinal Chemistry Letters . 2 . 1 . 48–52 . October 2010 . 21344069 . 3041981 . 10.1021/ml1002025 .
  14. Lauflumide and the enantiomers thereof, method for preparing same and therapeutic uses thereof . US . 20130295196 . 7 November 2013 . 2 May 2017 . Konofal E . NLS Pharmaceutics AG . Assistance Publique Hopitaux de Paris APHP .
  15. Halogenobenzhydrylsulfinylacetohydroxamic acids . US . 4489095 . 18 December 1984 . Lafon L . Cephalon France SAS .
  16. Web site: Acetamide, 2-bis(4-fluorophenyl)methylsulfinyl]- ]. PubChem . 18 August 2024.
  17. Web site: Investigations into the metabolism and elimination of flmodafinil and fladrafinil as well as their prevalence in elite sports . World Anti Doping Agency . 23 May 2024 . 18 August 2024.

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