Flmodafinil

Last updated

Flmodafinil
CRL-40,940.svg
Clinical data
Other namesCRL-40,941; CRL-40941; NLS-4; JBG01-41; JBG1-41; JBG1-041; Bisfluoromodafinil; Lauflumide; JBG1-048/JBG1-049; JBG01-048/JBG01-049 [1]
Identifiers
  • (2-Amino-2-oxoethyl)[bis(4-fluorophenyl)methyl]sulfoniumolate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C15H13F2NO2S
Molar mass 309.33 g·mol−1
3D model (JSmol)
  • C1=CC(=CC=C1C(C2=CC=C(C=C2)F)S(=O)CC(=O)N)F
  • InChI=1S/C15H13F2NO2S/c16-12-5-1-10(2-6-12)15(21(20)9-14(18)19)11-3-7-13(17)8-4-11/h1-8,15H,9H2,(H2,18,19)
  • Key:YEAQNUMCWMRYMU-UHFFFAOYSA-N

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]

Contents

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]

Pharmacology

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]

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.

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]

Related Research Articles

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<span class="mw-page-title-main">Adrafinil</span> Wakefulness-promoting drug

Adrafinil, sold under the brand name Olmifon, is a wakefulness-promoting medication that was formerly used in France to improve alertness, attention, wakefulness, and mood, particularly in the elderly. It was also used off-label by individuals who wished to avoid fatigue, such as night workers or others who needed to stay awake and alert for long periods of time. Additionally, the medication has been used non-medically as a novel vigilance-promoting agent.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

<span class="mw-page-title-main">Armodafinil</span> Eugeroic medication

Armodafinil, sold under the brand name Nuvigil, is a wakefulness-promoting medication which is used to treat excessive daytime sleepiness associated with obstructive sleep apnea, narcolepsy, and shift work disorder. It is also used off-label for certain other indications. The drug is taken by mouth.

<span class="mw-page-title-main">(+)-CPCA</span> Stimulant drug

(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine lacks the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.

<span class="mw-page-title-main">Difluoropine</span> Chemical compound

Difluoropine (O-620) is a stimulant drug synthesised from tropinone, which acts as a potent and selective dopamine reuptake inhibitor. Difluoropine is unique among the tropane-derived dopamine reuptake inhibitors in that the active stereoisomer is the (S) enantiomer rather than the (R) enantiomer, the opposite way round compared to natural cocaine. It is structurally related to benztropine and has similar anticholinergic and antihistamine effects in addition to its dopamine reuptake inhibitory action.

<span class="mw-page-title-main">Fluorenol</span> Chemical compound

Fluorenol, also known as hydrafinil, is an alcohol derivative of fluorene. In the most significant isomer, fluoren-9-ol or 9-hydroxyfluorene, the hydroxy group is located on the bridging carbon between the two benzene rings. Hydroxyfluorene can be converted to fluorenone by oxidation. It is a white-cream colored solid at room temperature.

<span class="mw-page-title-main">Eugeroic</span> Drug for wakefulness and alertness

A eugeroic, or eugregoric, also known as a vigilance-promoting agent, is a type of drug that increases vigilance. The term has been used inconsistently and in multiple ways in the scientific literature, either to refer specifically to modafinil-type wakefulness-promoting agents or to refer to wakefulness-promoting agents generally. It was first introduced in the French literature in 1987 as a descriptor for modafinil-like wakefulness-promoting drugs and for purposes of distinguishing such drugs from psychostimulants. However, the term "eugeroic" has not been widely adopted in the literature, and instead the term "wakefulness-promoting agent" has been more widely used, both for modafinil-type drugs and other agents.

<span class="mw-page-title-main">Fladrafinil</span> Wakefulness-promoting drug

Fladrafinil, also known as fluorafinil or as bisfluoroadrafinil, is a wakefulness-promoting agent related to modafinil that was never marketed. It is sold online and used non-medically as a nootropic.

<span class="mw-page-title-main">JHW-007</span> Atypical dopamine reuptake inhibitor

JHW-007 is a cocaine analogue and a high affinity atypical dopamine reuptake inhibitor that is being researched for the treatment of cocaine addiction. JHW-007 has been found to blunt the psychostimulant effects of cocaine and reduce self-administration in rodents. JHW-007 exposure has been shown to block the conditioned place preference effects of cocaine. JHW-007 may directly antagonize the autoregulatory dopamine D2 receptor, a hypothesis that was developed following the observation of JHW-007's ability to inhibit D2 receptor-mediated currents in the midbrain.

<span class="mw-page-title-main">Esmodafinil</span> Unmarketed enantiomer of modafinil

Esmodafinil (also known as (S)-modafinil or (+)-modafinil; developmental code name CRL-40983) is the enantiopure (S)-(+)-enantiomer of modafinil. Unlike armodafinil ((R)-(–)-modafinil), esmodafinil has never been marketed on its own.

<span class="mw-page-title-main">Modafiendz</span> Wakefulness-promoting drug related to modafinil

Modafiendz, also known as N-methyl-4,4-difluoromodafinil or as N-methylbisfluoromodafinil, is a wakefulness-promoting agent related to modafinil that was never marketed. It is sold online and used non-medically as a nootropic.

<span class="mw-page-title-main">RDS03-94</span> Dopamine reuptake inhibitor related to modafinil being developed for stimulant use disorder

RDS03-94, or RDS3-094, is an atypical dopamine reuptake inhibitor that was derived from the wakefulness-promoting agent modafinil.

<span class="mw-page-title-main">JJC8-088</span> Cocaine-like dopamine reuptake inhibitor derived from modafinil

JJC8-088 is a dopamine reuptake inhibitor (DRI) that was derived from the wakefulness-promoting agent modafinil.

(<i>S</i>)-MK-26 An atypical dopamine reuptake inhibitor with pro-motivational effects related to modafinil

(S)-MK-26 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It is closely related to two other modafinil analogues, (S,S)-CE-158 and (S)-CE-123.

<span class="mw-page-title-main">CE-158</span> Chemical compound

CE-158 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It is often but not always referred to as the enantiopure enantiomer (S,S)-CE-158 instead.

<span class="mw-page-title-main">JJC8-016</span> Abandoned drug

JJC8-016 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It was an early lead in the development of novel modafinil analogues with improved properties for potential use in the treatment of psychostimulant use disorder (PSUD).

<span class="mw-page-title-main">JJC8-091</span> Active component of a pharmaceutical drug

JJC8-091 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It is a lead compound for potential treatment of psychostimulant use disorder (PSUD) and is under development by Encepheal Therapeutics for use as a pharmaceutical drug.

<span class="mw-page-title-main">JJC8-089</span> Dopamine reuptake inhibitor related to modafinil

JJC8-089 is a dopamine reuptake inhibitor (DRI) that was derived from modafinil and is related to JJC8-016, JJC8-088, and JJC8-091. Its affinity (Ki) for the dopamine transporter (DAT) is 37.8 nM, for the norepinephrine transporter (NET) is 11,820 nM, for the serotonin transporter (SERT) is 6,800 nM, and for the sigma σ1 receptor is 2.24 nM. It also has significant affinity for several dopamine receptors. JJC8-089 has substantially higher affinity for the DAT than modafinil. The drug shows pro-motivational effects in animals. It was first described in the scientific literature by 2016.

References

  1. 1 2 3 4 5 6 7 8 9 10 Keighron JD, Giancola JB, Shaffer RJ, DeMarco EM, Coggiano MA, Slack RD, et al. (August 2019). "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. doi:10.1111/ejn.14256. PMC   8294075 . PMID   30402972.
  2. 1 2 3 4 5 6 7 Konofal E (August 2024). "From past to future: 50 years of pharmacological interventions to treat narcolepsy". Pharmacol Biochem Behav. 241: 173804. doi: 10.1016/j.pbb.2024.173804 . PMID   38852786. 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 ).
  3. 1 2 3 4 5 6 "Lauflumide - NLS Pharmaceutics Ltd". AdisInsight. Springer Nature Switzerland AG. 28 January 2024. Retrieved 17 August 2024.
  4. 1 2 3 "Pipeline". monsolfoundation.ch. 30 September 2022. Retrieved 17 August 2024.
  5. ↑ Sousa A, Dinis-Oliveira RJ (2020). "Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects". Subst Abus. 41 (2): 155–173. doi:10.1080/08897077.2019.1700584. PMID   31951804. 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
  6. ↑ Schifano F, Catalani V, Sharif S, Napoletano F, Corkery JM, Arillotta D, et al. (April 2022). "Benefits and Harms of 'Smart Drugs' (Nootropics) in Healthy Individuals". Drugs. 82 (6): 633–647. doi:10.1007/s40265-022-01701-7. PMID   35366192. [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].
  7. ↑ Dowling G, Kavanagh PV, Talbot B, O'Brien J, Hessman G, McLaughlin G, et al. (March 2017). "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" (PDF). Drug Test Anal. 9 (3): 518–528. doi:10.1002/dta.2142. PMID   27928893.
  8. 1 2 3 4 5 6 7 8 Luca G, Bandarabadi M, Konofal E, Lecendreux M, Ferrié L, Figadère B, et al. (2018). "Lauflumide (NLS-4) Is a New Potent Wake-Promoting Compound". Front Neurosci. 12: 519. doi: 10.3389/fnins.2018.00519 . PMC   6104159 . PMID   30158846. 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. 1 2 Zanettini C, Scaglione A, Keighron JD, Giancola JB, Lin SC, Newman AH, et al. (December 2019). "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. doi:10.1016/j.neuropharm.2018.11.034. PMC   8369976 . PMID   30481526. 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.
  10. 1 2 3 4 5 6 Giancola JB, Bonifazi A, Cao J, Ku T, Haraczy AJ, Lam J, et al. (December 2020). "Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability". European Journal of Medicinal Chemistry. 208: 112674. doi:10.1016/j.ejmech.2020.112674. PMC   7680422 . PMID   32947229.
  11. 1 2 Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH (February 2021). "Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder". Curr Opin Pharmacol. 56: 13–21. doi:10.1016/j.coph.2020.07.007. PMC   8247144 . PMID   32927246. 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].
  12. ↑ Ramsson ES, Howard CD, Covey DP, Garris PA (December 2011). "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. doi:10.1111/j.1471-4159.2011.07407.x. PMC   3213283 . PMID   21806614.
  13. 1 2 CA 1199916,Lafon L,"Benzhydrylsulfinylacetamide derivatives",published 28 January 1986,issued 28 January 1986, assigned to Cephalon France SAS
  14. ↑ Cao J, Prisinzano TE, Okunola OM, Kopajtic T, Shook M, Katz JL, et al. (October 2010). "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. doi:10.1021/ml1002025. PMC   3041981 . PMID   21344069.
  15. ↑ US 20130295196,Konofal E,"Lauflumide and the enantiomers thereof, method for preparing same and therapeutic uses thereof",published 7 November 2013,issued 2 May 2017, assigned to NLS Pharmaceutics AGand Assistance Publique Hopitaux de Paris APHP
  16. ↑ US 4489095,Lafon L,"Halogenobenzhydrylsulfinylacetohydroxamic acids",issued 18 December 1984, assigned to Cephalon France SAS
  17. ↑ "Acetamide, 2-[[bis(4-fluorophenyl)methyl]sulfinyl]-". PubChem. Retrieved 18 August 2024.
  18. ↑ "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. Retrieved 18 August 2024.
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