Eugeroic | |
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Drug class | |
![]() The chemical structure of modafinil, the prototypical drug of this class | |
Class identifiers | |
Synonyms | Eugrégorique; Eugregorique; Eugregoric; Vigilance-promoting agent |
Use | To increase wakefulness and arousal, to reduce sleepiness and sedation |
ATC code | N06B |
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]
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]
Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant and eugeroic 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.
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.
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.
Racetams, also sometimes known simply as pyrrolidones, are a class of drugs that share a pyrrolidone nucleus. Many, but not all, specifically have a 2-oxo-1-pyrrolidine acetamide (piracetam) nucleus. Some racetams, such as piracetam, aniracetam, oxiracetam, pramiracetam, and phenylpiracetam, are considered nootropics. Phenylpiracetam is also a stimulant. Others, such as levetiracetam, brivaracetam, and seletracetam, are anticonvulsants.
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.
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.
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.
A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.
A wakefulness-promoting agent (WPA), or wake-promoting agent, is a drug that increases wakefulness and arousal. 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. Wakefulness-promoting agents are used to treat narcolepsy and hypersomnia as well as to promote wakefulness and increase performance in healthy people.
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.
Flmodafinil, 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. 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.
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.
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.
MRZ-9547, also known as (R)-phenylpiracetam, (R)-phenotropil, or (R)-fonturacetam, is a selective dopamine reuptake inhibitor (IC50Tooltip half-maximal inhibitory concentration = 14.5 μM) that was developed by Merz Pharma. It is the (R)-enantiomer of the racetam and nootropic phenylpiracetam (phenotropil; fonturacetam).
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.
JJC8-088 is a dopamine reuptake inhibitor (DRI) that was derived from the wakefulness-promoting agent 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.
Armesocarb (developmental code name MLR-1019), also known as (R)-mesocarb or L-mesocarb, is a selective atypical dopamine reuptake inhibitor (DRI). It is currently under development for the treatment of Parkinson's disease and sleep disorders.
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
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).
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).
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