Wakefulness-promoting agent

Last updated
Wakefulness-promoting agent
Drug class
Modafinil.svg
The chemical structure of modafinil, a widely used wakefulness-promoting agent
Class identifiers
Synonyms Wakefulness-promoting agent; Wakefulness-promoting drug; Wakefulness promoting medication; Wake-promoting agent; Wake-promoting drug; Wake-promoting medication; WPA
UseTo increase wakefulness and arousal, to reduce sleepiness and sedation
Legal status
In Wikidata

A wakefulness-promoting agent (WPA), or wake-promoting agent, is a drug that increases wakefulness and arousal. [1] [2] [3] They are similar to but distinct from psychostimulants, which not only promote wakefulness but also produce other more overt central nervous system effects, such as improved mood, energy, and motivation. [1] [4] Wakefulness-promoting agents are used to treat narcolepsy and hypersomnia as well as to promote wakefulness and increase performance in healthy people. [5] [6] [7]

A variety of different classes of drugs have shown wakefulness-promoting effects, including: [8] [5] [3] [9]

Histamine and other histamine H1 receptor agonists also have wakefulness-promoting effects. [9] [17] [18] However, H1 receptor agonists as drugs are limited by their mediation of allergy-type symptoms. [18]

Certain other drugs are being studied as wakefulness-promoting agents as well, including GABAA receptor antagonists and negative allosteric modulators like clarithromycin, flumazenil, and pentylenetetrazol (pentetrazol), among others. [19]

Aside from the above-described wakefulness-promoting agents, the GHB and GABAB receptor agonist sodium oxybate or γ-hydroxybutyrate (GHB) has been used in the treatment of narcolepsy. [20] [8] [5] [3] Relatedly, some researchers have classified this drug as a stimulant-like agent. [20] However, GHB is taken at night and only results in improved wakefulness the next day following sleep. [20]

The related term "eugeroic" (or "eugregoric") means "vigilance-promoting". [5] It was introduced in 1987 in the French literature and has been used as an alternative term to refer to wakefulness-promoting drugs and to distinguish them from psychostimulants. [5] However, the term has usually been used to refer specifically to modafinil and its analogues, even to the exclusion of other wakefulness-promoting agents. [5] [21] [22] Moreover, the term has not been widely adopted in the scientific literature. [5] The discovery of wakefulness-promoting neurons and the orexin neuropeptides has prompted a terminological shift away from the concept of "vigilance-promoting" to "wakefulness-promoting". [5]

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

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.

Histamine H<sub>3</sub> receptor Mammalian protein found in Homo sapiens

Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons and control histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin.

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

Phenylpiracetam, also known as fonturacetam and sold under the brand names Phenotropil, Actitropil, and Carphedon among others, is a stimulant and nootropic medication used in Russia and certain other Eastern European countries in the treatment of cerebrovascular deficiency, depression, apathy, and attention, and memory problems, among other indications. It is also used in Russian cosmonauts to improve physical, mental, and cognitive abilities. The drug is taken by mouth.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

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

<span class="mw-page-title-main">Amineptine</span> Widely withdrawn tricyclic antidepressant

Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a lesser extent as a norepinephrine reuptake inhibitor.

<span class="mw-page-title-main">Nomifensine</span> Group of stereoisomers

Nomifensine, sold under the brand names Merital and Alival, is a norepinephrine–dopamine reuptake inhibitor (NDRI), i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters. This is a mechanism of action shared by some recreational drugs like cocaine and the medication tametraline (see DRI). Research showed that the (S)-isomer is responsible for activity.

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

Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist.

An H3 receptor antagonist is a type of antihistaminic drug used to block the action of histamine at H3 receptors.

<span class="mw-page-title-main">Levoamphetamine</span> CNS stimulant and isomer of amphetamine

Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination with dextroamphetamine in varying ratios under brand names like Adderall and Evekeo. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. Levoamphetamine is taken by mouth.

Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy. It is an inverse agonist of the histamine 3 (H3) receptor (an antihistamine drug specific to that kind of receptors). It represents the first commercially available medication in its class, so that the U.S. Food and Drug Administration (FDA) declares it a first-in-class medication. Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness. It was approved by the European Medicines Agency (EMA) in March 2016 for narcolepsy with or without cataplexy, and for excessive daytime sleepiness by the FDA in August 2019. The most common side effects include difficulty sleeping, nausea, and feeling worried.

<span class="mw-page-title-main">Norepinephrine releasing agent</span> Catecholaminergic type of drug

A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into the synapse. This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine therefore an increase in adrenergic neurotransmission.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.

<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">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">Solriamfetol</span> Medication used for the treatment of excessive sleepiness

Solriamfetol, sold under the brand name Sunosi, is a wakefulness-promoting medication used in the treatment of excessive sleepiness related to narcolepsy and sleep apnea. It is taken by mouth.

Samelisant (INNTooltip International Nonproprietary Name; developmental code name SUVN-G3031) is an experimental wakefulness-promoting agent acting as a selective histamine H3 receptor inverse agonist which is under development for the treatment of narcolepsy. It was also under development for the treatment of cognition disorders and Parkinson's disease, but no recent development has been reported for these indications. As of June 2024, samelisant is in phase 2 clinical trials for the treatment of narcolepsy.

References

  1. 1 2 3 Boutrel B, Koob GF (September 2004). "What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications". Sleep. 27 (6): 1181–1194. doi:10.1093/sleep/27.6.1181. PMID   15532213.
  2. ↑ 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.
  3. 1 2 3 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.
  4. ↑ Chang, Shen-Chieh; Shen, Winston W. (2013). "Stimulants, Wakefulness-promoting Agents, and Nonstimulant Attention Deficit Hyperactivity Disorder Medications". Journal of Experimental & Clinical Medicine. 5 (6): 210–216. doi:10.1016/j.jecm.2013.10.010.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 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.
  6. ↑ Clark I, Landolt HP (February 2017). "Coffee, caffeine, and sleep: A systematic review of epidemiological studies and randomized controlled trials". Sleep Med Rev. 31: 70–78. doi:10.1016/j.smrv.2016.01.006. PMID   26899133.
  7. ↑ Plumber N, Majeed M, Ziff S, Thomas SE, Bolla SR, Gorantla VR (May 2021). "Stimulant Usage by Medical Students for Cognitive Enhancement: A Systematic Review". Cureus. 13 (5): e15163. doi: 10.7759/cureus.15163 . PMC   8216643 . PMID   34178492.
  8. 1 2 3 4 5 6 7 8 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.
  9. 1 2 3 4 5 6 7 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.
  10. ↑ 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.{{cite book}}: CS1 maint: location (link)
  11. ↑ 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
  12. ↑ Jones-Tabah J, Mohammad H, Paulus EG, Clarke PB, Hébert TE (2021). "The Signaling and Pharmacology of the Dopamine D1 Receptor". Frontiers in Cellular Neuroscience. 15: 806618. doi: 10.3389/fncel.2021.806618 . PMC   8801442 . PMID   35110997.
  13. ↑ McCarthy AP, Svensson KA, Shanks E, Brittain C, Eastwood BJ, Kielbasa W, et al. (March 2022). "The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers". The Journal of Pharmacology and Experimental Therapeutics. 380 (3): 143–152. doi: 10.1124/jpet.121.000719 . PMID   34893551. S2CID   247363215.
  14. ↑ Jenner P, Mori A, Kanda T (November 2020). "Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson's disease?". Parkinsonism Relat Disord. 80 Suppl 1: S28–S36. doi: 10.1016/j.parkreldis.2020.09.022 . PMID   33349577.
  15. ↑ Lazarus M, Chen JF, Huang ZL, Urade Y, Fredholm BB (2019). "Adenosine and Sleep". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 253: 359–381. doi:10.1007/164_2017_36. ISBN   978-3-030-11270-7. PMID   28646346.
  16. ↑ Singh N, Wanjari A, Sinha AH (November 2023). "Effects of Nicotine on the Central Nervous System and Sleep Quality in Relation to Other Stimulants: A Narrative Review". Cureus. 15 (11): e49162. doi: 10.7759/cureus.49162 . PMC   10733894 . PMID   38130519.
  17. ↑ Thakkar MM (February 2011). "Histamine in the regulation of wakefulness". Sleep Med Rev. 15 (1): 65–74. doi:10.1016/j.smrv.2010.06.004. PMC   3016451 . PMID   20851648.
  18. 1 2 Panula P (2021). "Histamine receptors, agonists, and antagonists in health and disease". The Human Hypothalamus - Middle and Posterior Region. Handbook of Clinical Neurology. Vol. 180. pp. 377–387. doi:10.1016/B978-0-12-820107-7.00023-9. ISBN   978-0-12-820107-7. PMID   34225942.{{cite book}}: |journal= ignored (help)
  19. ↑ Takahashi, Tatsunori; Noriaki, Sakai; Matsumura, Mari; Li, Chenyu; Takahashi, Kayo; Nishino, Seiji (3 October 2018). "Advances in pharmaceutical treatment options for narcolepsy". Expert Opinion on Orphan Drugs. 6 (10): 597–610. doi:10.1080/21678707.2018.1521267. ISSN   2167-8707.
  20. 1 2 3 Ono T, Takenoshita S, Nishino S (September 2022). "Pharmacologic Management of Excessive Daytime Sleepiness". Sleep Med Clin. 17 (3): 485–503. doi:10.1016/j.jsmc.2022.06.012. PMID   36150809.
  21. ↑ Urban AE, Cubała WJ (February 2020). "The role of eugeroics in the treatment of affective disorders". Psychiatr Pol. 54 (1): 21–33. doi: 10.12740/PP/OnlineFirst/90687 . PMID   32447354.
  22. ↑ 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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