Eugeroic

Eugeroic
Drug class
The chemical structure of modafinil, the prototypical drug of this class
Class identifiers
SynonymsEugrégorique; Eugregorique; Eugregoric; Vigilance-promoting agent
UseTo increase wakefulness and arousal, to reduce sleepiness and sedation
ATC codeN06B
Legal status
In Wikidata

A eugeroic, or eugregoric, also known as a vigilance-promoting agent, is a type of drug that increases vigilance (that is, alertness and/or wakefulness).[1][2][3][4] 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.[1][5][6][7] 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.[1] However, the term "eugeroic" has not been widely adopted in the literature, and instead the term "wakefulness-promoting agent" (and variations thereof) has been more widely used, both for modafinil-type drugs and other agents.[1][8][9][10]

Eugeroics, in the sense of modafinil-type wakefulness promoting agents, include modafinil itself, armodafinil, and adrafinil, among others.[9] They are medically indicated for the treatment of certain sleep disorders, including excessive daytime sleepiness (EDS) in narcolepsy or obstructive sleep apnea (OSA).[3][4] Eugeroics are also often prescribed off-label for the treatment of EDS in idiopathic hypersomnia.[11] In contrast to classical psychostimulants, such as amphetamine and methylphenidate, which are also used in the treatment of these disorders, eugeroics typically do not produce euphoria, and, consequently, have lower misuse potential.[3][4][12]

Modafinil and armodafinil are thought to act as selective, weak, atypical dopamine reuptake inhibitors (DRIs).[13][3][4] However, additional actions are also possible and have not been ruled out.[13] Adrafinil acts as a prodrug of modafinil and hence shares its mechanism of action.[13] Certain other drugs acting as atypical DRIs with known or potential wakefulness-promoting effects include solriamfetol (also a norepinephrine reuptake inhibitor),[14][15] vanoxerine,[16] phenylpiracetam,[17][18][19] and mesocarb.[20][21][22][23] Other wakefulness-promoting agents act in a variety of other ways.[16][1][10][24]

List of eugeroics

Marketed

  • Armodafinil (Nuvigil, CRL-40982, CEP-10952, (R)-modafinil) – the (R)-enantiomer of modafinil
  • Modafinil (Provigil, Alertec, Modavigil, CRL-40476) – a racemic mixture of armodafinil and esmodafinil

Discontinued

  • Adrafinil (Olmifon, CRL-40028, N-hydroxymodafinil) – a hydroxy-substituted derivative and prodrug of modafinil

Never marketed

  • Esmodafinil (CRL-40983, (S)-modafinil) – the (S)-enantiomer of modafinil
  • Fladrafinil (CRL-40941, fluorafinil, bisfluoroadrafinil) – a bisfluoro-substituted derivative of adrafinil
  • Flmodafinil (CRL-40940, NLS-4, JBG01-41, bisfluoromodafinil, lauflumide) – a bisfluoro-sbustituted derivative of modafinil
  • Fluorenol ("hydrafinil") – a novel eugeroic structurally unrelated to modafinil and its analogues
  • Modafiendz (methylbisfluoromodafinil) – a methyl and bisfluoro-substituted derivative of modafinil

Novel eugeroics

See also: List of modafinil analogues and derivatives

The pharmaceutical company Cephalon, the original United States market rights holder of modafinil, has demonstrated initiative in the development of a successor to the prototypical eugeroic.[25] Of the more than twenty compounds preclinically tested in Cephalon's three-part drug discovery series, the compound fluorenol was selected as a lead.[26] Fluorenol was found to induce wakefulness to a greater degree than modafinil, despite possessing a lower affinity for the dopamine transporter (DAT).[26] Many other modafinil analogues have also subsequently been developed, not specifically as wakefulness-promoting agents but for treatment of conditions like psychostimulant use disorder and motivational disorders.[27][28][29][17]

References

  1. ^ a b c d e 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.
  2. ^ Milgram, Norton W.; Callahan, Heather; Siwak, Christina (2006). "Adrafinil: A Novel Vigilance Promoting Agent". CNS Drug Reviews. 5 (3): 193–212. doi:10.1111/j.1527-3458.1999.tb00100.x. ISSN 1080-563X.
  3. ^ a b c d "Provigil: Prescribing information" (PDF). United States Food and Drug Administration. Cephalon, Inc. January 2015. Retrieved 16 August 2015.
  4. ^ a b c d "Nuvigil: Prescribing information" (PDF). United States Food and Drug Administration. Cephalon, Inc. April 2015. Retrieved 16 August 2015.
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  6. ^ Castillo PR (August 2023). "Clinical Neurobiology of Sleep and Wakefulness". Continuum (Minneap Minn). 29 (4): 1016–1030. doi:10.1212/CON.0000000000001260. PMID 37590820.
  7. ^ Lagarde D, Batejat D (1995). "Some measures to reduce effects of prolonged sleep deprivation". Neurophysiol Clin. 25 (6): 376–385. doi:10.1016/0987-7053(96)84911-2. PMID 8904200.
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  9. ^ a b Dell'Osso B, Dobrea C, Cremaschi L, Arici C, Altamura AC (December 2014). "Wake-promoting pharmacotherapy for psychiatric disorders". Curr Psychiatry Rep. 16 (12): 524. doi:10.1007/s11920-014-0524-2. PMID 25312027.
  10. ^ a b Zhan S, Ye H, Li N, Zhang Y, Cheng Y, Wang Y, Hu S, Hou Y (2023). "Comparative Efficacy and Safety of Multiple Wake-Promoting Agents for the Treatment of Excessive Daytime Sleepiness in Narcolepsy: A Network Meta-Analysis". Nat Sci Sleep. 15: 217–230. doi:10.2147/NSS.S404113. PMC 10112483. PMID 37082610.
  11. ^ "Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin" (PDF). American Academy of Sleep Medicine (AASM). September 2007.
  12. ^ Taneja, Indu; Haman, Kirsten; Shelton, Richard C.; Robertson, David (February 2007). "A randomized, double-blind, crossover trial of modafinil on mood". Journal of Clinical Psychopharmacology. 27 (1): 76–79. doi:10.1097/jcp.0b013e31802eb7ea. ISSN 0271-0749. PMID 17224718. S2CID 40801601.
  13. ^ a b c Hersey M, Tanda G (2024). "Modafinil, an atypical CNS stimulant?". Pharmacological Advances in Central Nervous System Stimulants. Adv Pharmacol. Vol. 99. pp. 287–326. doi:10.1016/bs.apha.2023.10.006. ISBN 978-0-443-21933-7. PMID 38467484.
  14. ^ Ngo Q, Plante DT (19 September 2022). "An Update on the Misuse and Abuse Potential of Pharmacological Treatments for Central Disorders of Hypersomnolence". Current Sleep Medicine Reports. 8 (4): 147–159. doi:10.1007/s40675-022-00227-4. ISSN 2198-6401.
  15. ^ Yang J, Gao J (August 2019). "Solriamfetol for the treatment of excessive daytime sleepiness associated with narcolepsy". Expert Rev Clin Pharmacol. 12 (8): 723–728. doi:10.1080/17512433.2019.1632705. PMID 31215815.
  16. ^ a b Nishino, Seiji; Kotorii, Nozomu (2016). "Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics". Narcolepsy. Cham: Springer International Publishing. pp. 307–329. doi:10.1007/978-3-319-23739-8_22. ISBN 978-3-319-23738-1.
  17. ^ a b Salamone JD, Correa M (January 2024). "The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine". Annu Rev Psychol. 75: 1–32. doi:10.1146/annurev-psych-020223-012208. hdl:10234/207207. PMID 37788571.
  18. ^ Veinberg G, Vavers E, Orlova N, Kuznecovs J, Domracheva I, Vorona M, Zvejniece L, Dambrova M (2015). "Stereochemistry of phenylpiracetam and its methyl derivative: improvement of the pharmacological profile". Chemistry of Heterocyclic Compounds. 51 (7): 601–606. doi:10.1007/s10593-015-1747-9. ISSN 0009-3122. Phenylpiracetam was originally designed as a nootropic drug for the sustenance and improvement of the physical condition and cognition abilities of Soviet space crews.2 Later, especially during the last decade, phenylpiracetam was introduced into general clinical practice in Russia and in some Eastern European countries. The possible target receptors and mechanisms for the acute activity of this drug remained unclear, until very recently it was found that (R)-phenylpiracetam (5) (MRZ-9547) is a selective dopamine transporter inhibitor that moderately stimulates striatal dopamine release.19
  19. ^ Sommer S, Danysz W, Russ H, Valastro B, Flik G, Hauber W (December 2014). "The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats". The International Journal of Neuropsychopharmacology. 17 (12): 2045–2056. doi:10.1017/S1461145714000996. PMID 24964269. Here, we tested the effects of MRZ-9547 [...], and its l-enantiomer MRZ-9546 on effort-related decision making in rats. The racemic form of these compounds referred to as phenotropil has been shown to stimulate motor activity in rats (Zvejniece et al., 2011) and enhance physical capacity and cognition in humans (Malykh and Sadaie, 2010). [...] MRZ-9547 turned out to be a DAT inhibitor as shown by displacement of binding of [125I] RTI-55 (IC50 = 4.82 ± 0.05 μM, n=3) to human recombinant DAT expressed in CHO-K1 cells and inhibition of DA uptake (IC50 = 14.5 ± 1.6 μM, n=2) in functional assays in the same cells. It inhibited norepinephrine transporter (NET) with an IC50 of 182 μM (one experiment in duplicate). The potencies for the l-enantiomer MRZ-9546 were as follows: DAT binding (Ki = 34.8 ± 14.8 μM, n=3), DAT function (IC50 = 65.5 ± 8.3 μM, n=2) and NET function (IC50 = 667 μM, one experiment performed in duplicate).
  20. ^ Nepal B, Das S, Reith ME, Kortagere S (2023). "Overview of the structure and function of the dopamine transporter and its protein interactions". Front Physiol. 14: 1150355. doi:10.3389/fphys.2023.1150355. PMC 10020207. PMID 36935752.
  21. ^ Nguyen H, Cheng MH, Lee JY, Aggarwal S, Mortensen OV, Bahar I (2024). "Allosteric modulation of serotonin and dopamine transporters: New insights from computations and experiments". Curr Res Physiol. 7: 100125. doi:10.1016/j.crphys.2024.100125. PMC 11148570. PMID 38836245.
  22. ^ Aggarwal S, Cheng MH, Salvino JM, Bahar I, Mortensen OV (June 2021). "Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb as an Allosteric Modulator of the Human Dopamine Transporter". Biomedicines. 9 (6): 634. doi:10.3390/biomedicines9060634. PMC 8227285. PMID 34199621.
  23. ^ Macolino-Kane, Christine M.; Ciallella, John R.; Lipinski, Christopher A.; Reaume, Andrew G. (14 July 2017). "Phenotypic Screening". Drug Repositioning (PDF). Frontiers in Neurotherapeutics. Boca Raton: CRC Press, [2017]: CRC Press. p. 121–145. doi:10.4324/9781315373669-7. ISBN 978-1-315-37366-9. Finally, [mesocarb] promotes wakefulness and therefore is anticipated to address the excessive daytime sleepiness (EDS) associated with PD (Mitler et al. 2000; Gjerstad et al. 2002; Larsen 2003; Arnulf 2005; Lökk 2010), which is a significant unmet medical need in this patient population. Melior's further investigations showed that the therapeutic activity described here was greatest when administering optimal dose levels of the active l-enantiomer (MLR-1019 [armesocarb]) compared to optimal dose levels of the racemic mixture (sydnocarb).{{cite book}}: CS1 maint: location (link)
  24. ^ Thorpy MJ, Bogan RK (April 2020). "Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications". Sleep Med. 68: 97–109. doi:10.1016/j.sleep.2019.09.001. PMID 32032921.
  25. ^ Dunn, Derek; Hostetler, Greg; Iqbal, Mohamed; Messina-McLaughlin, Patricia; Reiboldt, Alyssa; Lin, Yin Guo; Gruner, John; Bacon, Edward R.; Ator, Mark A.; Chatterjee, Sankar (2012-03-15). "Wake-promoting agents: search for next generation modafinil: part I". Bioorganic & Medicinal Chemistry Letters. 22 (6): 2312–2314. doi:10.1016/j.bmcl.2011.12.099. ISSN 1464-3405. PMID 22264475.
  26. ^ a b Dunn, Derek; Hostetler, Greg; Iqbal, Mohamed; Marcy, Val R.; Lin, Yin Guo; Jones, Bruce; Aimone, Lisa D.; Gruner, John; Ator, Mark A.; Bacon, Edward R.; Chatterjee, Sankar (2012-06-01). "Wake promoting agents: Search for next generation modafinil, lessons learned: Part III". Bioorganic & Medicinal Chemistry Letters. 22 (11): 3751–3753. doi:10.1016/j.bmcl.2012.04.031. ISSN 0960-894X. PMID 22546675.
  27. ^ Hersey M, Bacon AK, Bailey LG, Coggiano MA, Newman AH, Leggio L, Tanda G (2021). "Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?". Front Neurosci. 15: 656475. doi:10.3389/fnins.2021.656475. PMC 8187604. PMID 34121988.
  28. ^ 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.
  29. ^ Aggarwal S, Mortensen OV (2023). "Discovery and Development of Monoamine Transporter Ligands". Drug Development in Psychiatry. Advances in Neurobiology. Vol. 30. pp. 101–129. doi:10.1007/978-3-031-21054-9_4. ISBN 978-3-031-21053-2. PMC 10074400. PMID 36928847. {{cite book}}: |journal= ignored (help)