CRL-40,940

Last updated

CRL-40,940
CRL-40,940.svg
Clinical data
Other namesCRL-40,941; CRL-40941; NLS-4; 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), 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. [2] [8] It has been found to block the dopamine transporter by 83%, to a greater extent than methylphenidate without unfavorable concomitant adrenergic effects. [8] The drug is an atypical dopamine reuptake inhibitor similarly to modafinil. [10] [1] [9]

The affinities for the dopamine transporter of flmodafinil's enantiomers and modafinil have been studied. [1] 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] 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] [11]

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. [10] [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] [12] [13] [14] [15] It appears to have first been patented in the 1980s. [16] [12]

Research

The pharmacokinetics of flmodafinil are being studied. [17]

Related Research Articles

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

Modafinil, sold under the brand name Provigil among others, is a wakefulness-promoting medication used primarily to treat narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks. Modafinil is also approved for stimulating wakefulness in people with sleep apnea and shift work sleep disorder. It is taken by mouth. Modafinil is not approved by the US Food and Drug Administration (FDA) for use in people under 17 years old.

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">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

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

Armodafinil (trade name Nuvigil) is the enantiopure compound of the eugeroic modafinil (Provigil). It consists of only the (R)-(−)-enantiomer of the racemic modafinil. Armodafinil is produced by the pharmaceutical company Cephalon Inc. and was approved by the U.S. Food and Drug Administration (FDA) in June 2007. In 2016, the FDA granted Mylan rights for the first generic version of Cephalon's Nuvigil to be marketed in the U.S.

<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">Troparil</span> Chemical compound

Troparil is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor, but is less potent as a serotonin reuptake inhibitor, and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring through a non-hydrolyzable carbon-carbon bond. The lack of an ester linkage removes the local anesthetic action from the drug, so troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine. The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.

<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">Narcolepsy</span> Human sleep disorder

Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM sleep. The pentad symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep related hallucinations, sleep paralysis, disturbed nocturnal sleep (DNS) and cataplexy. There are two recognized forms of narcolepsy, narcolepsy type 1 and type 2. Narcolepsy type 1 (NT1) can be clinically characterized by symptoms of EDS and cataplexy, and/or will have CSF orexin levels of less than 110 pg/ml. Cataplexy are transient episodes of aberrant tone, most typically loss of tone, that can be associated with strong emotion. In pediatric onset narcolepsy, active motor phenomena are not uncommon. Cataplexy may be mistaken for syncope, tic disorder or seizures. Narcolepsy type 2 (NT2) does not have features of cataplexy and CSF orexin levels are normal. Sleep related hallucinations, also known as hypnogogic and hypnopompic are vivid hallucinations that can be auditory, visual or tactile and may occur independent of or in combination with an inability to move. People with narcolepsy tend to sleep about the same number of hours per day as people without it, but the quality of sleep is typically compromised. Narcolepsy is a clinical syndrome of hypothalamic disorder, but the exact cause of narcolepsy is unknown, with potentially several causes. A leading consideration for the cause of narcolepsy type 1 is that it is an autoimmune disorder. Proposed pathophysiology as an autoimmune disease suggest antigen presentation by DQ0602 to specific CD4+ T cells resulting in CD8+ T-cell activation and consequent injury to orexin producing neurons. Familial trends of narcolepsy are suggested to be higher than previously appreciated. Familial risk of narcolepsy among first degree relatives is high. Relative risk for narcolepsy in a first degree relative has been reported to be 361.8. However, it is important to note that there is a spectrum of symptoms found in this study, including asymptomatic abnormal sleep test findings to significantly symptomatic.

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

Tropoxane (O-1072) is an aryloxytropane derivative drug developed by Organix Inc., which acts as a stimulant and potent dopamine and serotonin reuptake inhibitor. It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link, demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known. On the other hand, many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed. Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).

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

Eugeroics, also known as wakefulness-promoting agents and wakefulness-promoting drugs, are a class of drugs that promote wakefulness and alertness. They are medically indicated for the treatment of certain sleep disorders including excessive daytime sleepiness (EDS) in narcolepsy or obstructive sleep apnea (OSA). Eugeroics are also often prescribed off-label for the treatment of EDS in idiopathic hypersomnia. In contrast to classical psychostimulants, such as methylphenidate and amphetamine, which are also used in the treatment of these disorders, eugeroics typically do not produce marked euphoria, and, consequently, have a lower addictive potential.

<span class="mw-page-title-main">Norepinephrine–dopamine reuptake inhibitor</span> Drug that inhibits the reuptake of norepinephrine and dopamine

A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson's disease. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.

<span class="mw-page-title-main">JZ-IV-10</span> Chemical compound

JZ-IV-10 is a piperidine derivative related to cocaine which acts as a highly potent serotonin–norepinephrine–dopamine reuptake inhibitor. The eugeroic modafinil was used as a lead to fuel this compound's discovery.

<span class="mw-page-title-main">CRL-40,941</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">Modafinil acid</span> Chemical compound

Modafinil acid (code name CRL-40467), also known as modafinilic acid or modafinil carboxylate, is one of the two major metabolites of modafinil – the other being modafinil sulfone. Modafinil acid is also a metabolite of the modafinil prodrug, adrafinil, and the (R)-(–)-enantiomer is a metabolite of armodafinil, the (R)-(–)-enantiomer of modafinil. Between 30 - 60% of modafinil is converted to modafinil acid and its half life is roughly half that of modafinil (about 7 hours). Modafinil acid seems to be inactive, and similarly to modafinil sulfone, does not appear to contribute to the wakefulness-promoting/psychostimulant effects of modafinil.

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

Modafinil sulfone (code name CRL-41056) is an achiral, oxidized metabolite of modafinil, a wakefulness-promoting agent. It is one of two major circulating metabolites of modafinil, the other being modafinil acid. Modafinil sulfone is also a metabolite of the modafinil prodrug, adrafinil. Modafinil sulfone is also a metabolite of armodafinil, the (R)-(–)-enantiomer of modafinil, as oxidation to the sulfone removes the chiral center at the sulfur atom. Modafinil sulfone has been described as inactive, and similarly to modafinil acid, does not appear to contribute to the wakefulness-promoting effects of modafinil. However, like modafinil, modafinil sulfone was found to show anticonvulsant properties in animals, indicating that it does possess some biological activity.

<span class="mw-page-title-main">CE-123</span> Designer drug, analog of modafinil

CE-123 is an analog of modafinil, the most researched of a series of structurally related heterocyclic derivatives. In animal studies, CE-123 was found to improve performance on tests of learning and memory in a manner consistent with a nootropic effect profile.

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

JHW-007 is a cocaine analog 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 psychostimulatory 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 is the enantiopure isolation of the (S) enantiomer of modafinil. Unlike armodafinil, esmodafinil has never been marketed on its own.

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. 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 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].
  11. ↑ 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.
  12. 1 2 CA 1199916,Lafon L,"Benzhydrylsulfinylacetamide derivatives",published 28 January 1986,issued 28 January 1986, assigned to Cephalon France SAS
  13. ↑ 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.
  14. ↑ 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
  15. ↑ US 4489095,Lafon L,"Halogenobenzhydrylsulfinylacetohydroxamic acids",issued 18 December 1984, assigned to Cephalon France SAS
  16. ↑ "Acetamide, 2-[[bis(4-fluorophenyl)methyl]sulfinyl]-". PubChem. Retrieved 18 August 2024.
  17. ↑ "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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