CE-158

Last updated

CE-158
CE-158.svg
Clinical data
Other names(S,S)-CE-158; S,S-CE-158
Drug class Atypical dopamine reuptake inhibitor
Identifiers
  • 5-(3-bromophenyl)-phenylmethyl sulfinylmethyl-1,3-thiazole
PubChem CID
Chemical and physical data
Formula C17H14BrNOS2
Molar mass 392.33 g·mol−1
3D model (JSmol)
  • C1=CC=C(C=C1)C(C2=CC(=CC=C2)Br)S(=O)CC3=CN=CS3
  • InChI=1S/C17H14BrNOS2/c18-15-8-4-7-14(9-15)17(13-5-2-1-3-6-13)22(20)11-16-10-19-12-21-16/h1-10,12,17H,11H2
  • Key:KWWHBBCVAQTAFQ-UHFFFAOYSA-N

CE-158 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil. [1] [2] [3] [4] [5] It is often but not always referred to as the enantiopure enantiomer (S,S)-CE-158 instead. [2] [3] [5]

CE-158 is a highly selective DRI with much greater potency than modafinil. [3] [5] As (S,S)-CE-158, its inhibitory potencies (IC50 Tooltip half-maximal inhibitory concentration) at the monoamine transporters are 227 nM at the dopamine transporter (DAT), 11,970 nM at the norepinephrine transporter (NET) (53-fold lower), and inactive at the serotonin transporter (SERT). [5]

The drug shows pro-motivational effects in animals and reverses tetrabenazine-induced motivational deficits. [1] It increases dopamine levels in the nucleus accumbens, blocks amphetamine-induced dopamine release in vitro , shows no effect on locomotor activity with acute or repeated administration except at a high dose, and enhances learning in animals. [3] [2] [5]

CE-158 was first described by 2020. [5] It is closely related to CE-123, an earlier modafinil analogue. [4] [5] CE-158 and related agents are of interest in the potential treatment of motivational disorders, psychostimulant use disorder (PSUD), and Alzheimer's disease. [1] [2] [3] [4] [5]

See also

Related Research Articles

<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">Tetrabenazine</span> Medication for hyperkinetic movement disorders

Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the U.S. Food and Drug Administration approved the use of tetrabenazine to treat chorea associated with Huntington's disease. Although other drugs had been used "off label," tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s.

<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">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.

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

Preladenant is a drug that was developed by Schering-Plough which acted as a potent and selective antagonist of the adenosine A2A receptor. It was being researched as a potential treatment for Parkinson's disease. Positive results were reported in Phase II clinical trials in humans, but it did not prove itself to be more effective than a placebo during Phase III trials, and so was discontinued in May 2013.

<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">JHW-007</span> Atypical dopamine reuptake inhibitor

JHW-007 is a cocaine analogue 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 psychostimulant 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 (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">PRX-14040</span> Dopamine reuptake inhibitor

PRX-14040 is a selective dopamine reuptake inhibitor that was developed by Prexa Pharmaceuticals. It has 28-fold selectivity for the dopamine transporter over the norepinephrine transporter. Similarly to various other dopamine reuptake inhibitors, the drug has been found to reverse motivational deficits induced by the dopamine depleting agent tetrabenazine in animals.

<span class="mw-page-title-main">MRZ-9547</span> Dopamine reuptake inhibitor that was under development for fatigue in Parkinsons disease

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).

<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.

A pro-motivational agent is a drug which increases motivation. They can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD), as well as in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, for instance due to stroke, traumatic brain injury, or neurodegenerative diseases. They are also used non-medically by healthy people to increase motivation and productivity, for instance in educational contexts.

(<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">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).

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.

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

  1. 1 2 3 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): 1–32. doi:10.1146/annurev-psych-020223-012208. PMID   37788571. Several atypical DAT inhibitors have been successful at reversing the effects of TBZ at doses that increase extracellular DA as measured by microdialysis, including CT-005404 (Rotolo et al. 2021), and the modafinil analogs CE-123 (Rotolo et al. 2019), CE-158 (Rotolo et al. 2020), and MK-26 (Kouhnavardi et al. 2022). [...] Furthermore, several drugs that inhibit DAT, when administered on their own, increase selection of high-effort PROG lever pressing in rats tested on the PROG/chow choice task, including bupropion (Randall et al. 2015); lisdexamfetamine (Yohn et al. 2016e); PRX-14040 (Yohn et al. 2016d); GBR 12909 (Yohn et al. 2016c); CE-123, CE-158, and CT-5404 (Rotolo et al. 2019, 2020, 2021); and MK-26 (Kouhnavardi et al. 2022).
  2. 1 2 3 4 Treadway MT, Salamone JD (2022). "Vigor, Effort-Related Aspects of Motivation and Anhedonia". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 58. Cham: 325–353. doi:10.1007/7854_2022_355. ISBN   978-3-031-09682-2. PMID   35505057. Recent papers have assessed the effort-related effects of the novel atypical DAT inhibitors (S)-CE-123, (S,S)-CE158, and CT-005404. All three compounds reversed the low-effort bias induced by [tetrabenazine (TBZ)], and also increased selection of high-effort PROG lever pressing while decreasing chow intake (Rotolo et al. 2019, 2020, 2021). These compounds also produced modest but significant increases in extracellular DA in nucleus accumbens core, [...] atypical DAT inhibitors offer promise as potential treatments for effort-related motivational symptoms.
  3. 1 2 3 4 5 Hersey M, Bartole MK, Jones CS, Newman AH, Tanda G (July 2023). "Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors". Molecules. 28 (13): 5270. doi: 10.3390/molecules28135270 . PMC   10343811 . PMID   37446929. S,S-CE-158, a highly DAT-selective and atypical DAT inhibitor, demonstrated an ability to stabilize recognition memory during the information acquisition process in a dose-dependent manner in mice [193]. S,S-CE-158 induced a substantial and sustained increase in mice extracellular nucleus accumbens DA [193,194] but showed no significant effect on locomotor activity following acute or repeated exposure [194]. In addition, S,S-CE-158 attenuated the dopaminergic releasing effects of amphetamine in cells stably expressing hDAT and enhanced learning acquisition responses and neuronal activity in rats [194]. Furthermore, it was recently reported that only a high dose (20 mg/kg) of S,S-CE-158 increased locomotor activity in mice, and that a subthreshold dose (10 mg/kg) rescued motor learning deficits propagated by dopaminergic mGluR5 silencing, suggesting a role in DAT trafficking [195]. Therefore, understanding the effects of S,S-CE-158 in both males and females in animal models of PSUD will be very interesting.
  4. 1 2 3 Shaikh A, Ahmad F, Teoh SL, Kumar J, Yahaya MF (2023). "Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease". Front Cell Neurosci. 17: 1292858. doi: 10.3389/fncel.2023.1292858 . PMC   10679733 . PMID   38026688. Due to their high DAT specificity, synthetic modafinil analogs like R-modafinil, S-CE-123 (S-5-((benzhydrylsulfinyl)methyl) thiazole), S,S-CE158 (5-(((S)-((S)-(3-bromophenyl)(phenyl) methyl)sulfinyl)methyl)thiazole), and S-MK-26 ((S)-5-(((B(3- chlorophenyl)methyl)sulphinyl)methyl)thiazole) do not exert any effect on the reward pathway, making them less likely to cause addiction, abuse or withdrawal symptoms compared to the parent drug and other non-specific counterparts (Kristofova et al., 2018; Sagheddu et al., 2020; Hazani et al., 2022; Kouhnavardi et al., 2022).
  5. 1 2 3 4 5 6 7 8 Rotolo RA, Kalaba P, Dragacevic V, Presby RE, Neri J, Robertson E, et al. (November 2020). "Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding". Psychopharmacology (Berl). 237 (11): 3459–3470. doi:10.1007/s00213-020-05625-6. PMC   7572767 . PMID   32770257.
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