List of modafinil analogues and derivatives

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Chemical structure of modafinil. Modafinil.svg
Chemical structure of modafinil.

This page lists chemical compounds similar to modafinil, known as modafinil analogues and derivatives. These are structural analogues and derivatives of modafinil, a drug that affects dopamine levels in the brain in an unusual way (atypical dopamine reuptake inhibitor or DRI). Modafinil is a drug that helps keep people awake and alert (wakefulness-promoting agent or "eugeroic"). [1] [2]

Most of the listed modafinil analogues are drugs that specifically target dopamine reuptake (reabsorption of a neurotransmitter by a neurotransmitter transporter) with stronger effects (selective DRIs with improved potency) compared to modafinil. [3] [2] [4] The modafinil analogues are of interest in the potential treatment of a condition involving the misuse of stimulant drugs (psychostimulant use disorder or PSUD), as drugs that help increase motivation (pro-motivational agents) to treat motivational disorders, [4] [5] [6] and for treatment of neurodegenerative diseases such as Alzheimer's disease. [3] [2] [7] [8]

Modafinil analogues acting as DRIs include both drugs similar to modafinil that affect dopamine without causing stimulant effects (atypical modafinil-like non-psychostimulant DRIs) such as flmodafinil and JJC8-016 and drugs that affect dopamine in a way similar to cocaine (classical or typical cocaine-like DRIs) such as JJC8-088. Besides their potential medical use, modafinil analogues, including adrafinil, flmodafinil, fladrafinil, and modafiendz, are also sold online as substances that are believed to improve cognitive functions such as memory and focus (nootropics or "cognitive enhancers"). [1] [9] [10] [11]

A limitation of some modafinil analogues such as JJC8-016 is blocking a specific protein (hERG) that can lead to heart problems (potent inhibition of the hERG antitarget and predicted cardiotoxicity). [8] [2] [12] [13] [14]

List of modafinil analogues and derivatives

In addition to the above, further modafinil analogues have also been described. [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [15] [54]

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">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">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">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

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">RTI-113</span> Chemical compound

RTI(-4229)-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor (DRI). It has been suggested as a possible substitute drug for the treatment of cocaine addiction. "RTI-113 has properties that make it an ideal medication for cocaine abusers, such as an equivalent efficacy, a higher potency, and a longer duration of action as compared to cocaine." Replacing the methyl ester in RTI-31 with a phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.

<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">Flmodafinil</span> Wakefulness-promoting drug/Dopamine reuptake inhibitor

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.

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

CE-123, or as the active enantiomer (S)-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. (S)-CE-123 has pro-motivational effects in animals, reverses tetrabenazine-induced motivational deficits, and could be useful in the treatment of motivational disorders in humans.

<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.

CT-005404, or CT-5404, is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. It shows pro-motivational effects in animals and reverses motivational deficits induced by tetrabenazine and interleukin-1β. CT-005404 is described as being orally active in animals and having a long duration of action. It is under development by Chronos Therapeutics for treatment of motivational disorders. The drug was first described by 2018.

<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

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