Mesocarb

Last updated

Mesocarb
Mesocarb.svg
Clinical data
Trade names Sidnocarb, Sydnocarb, Synocarb
Other namesFensidnimine; Pharmaneocarb; Sydnocarbum; MLR-1017; N-Phenylcarbamoyl-3-(β-phenylisopropyl)sydnonimine; 3-(β-Phenylisopropyl)-N-phenylcarbamoylsydnonimine
Routes of
administration 		Oral
Drug class Atypical dopamine reuptake inhibitor
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Metabolism Hepatic
Excretion Renal
Identifiers
  • 5-(Phenylcarbamoylimino)-3-(1-phenylpropan-2-yl)-5H-1,2,3-oxadiazol-3-ium-2-ide
CAS Number
PubChem CID
PubChemSID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C18H18N4O2
Molar mass 322.368 g·mol−1
3D model (JSmol)
  • O=C(\N=C1/C=[N+](\[N-]O1)C(C)Cc2ccccc2)Nc3ccccc3
  • InChI=1S/C18H18N4O2/c1-14(12-15-8-4-2-5-9-15)22-13-17(24-21-22)20-18(23)19-16-10-6-3-7-11-16/h2-11,13-14H,12H2,1H3,(H,19,23)/b20-17+ Yes check.svgY
  • Key:DMHQLXUFCQSQQQ-LVZFUZTISA-N Yes check.svgY
   (verify)

Mesocarb, sold under the brand name Sidnocarb or Sydnocarb and known by the developmental code name MLR-1017, is a psychostimulant medication which has been used in the treatment of psychiatric disorders and for a number of other indications in the Soviet Union and Russia. [2] [3] [4] [5] It is currently under development for the treatment of Parkinson's disease and sleep disorders. [6] [7] It is taken by mouth.

Contents

The drug is a selective dopamine reuptake inhibitor (DRI). [8] [9] [10] [11] It is an unusual and unique DRI, acting as a negative allosteric modulator and non-competitive inhibitor of the dopamine transporter (DAT). [8] [9] [10] Chemically, mesocarb contains amphetamine within its structure but has been modified and extended at the amine with a sydnone imine-containing moiety. [12] [2] [3]

Mesocarb was first described by 1971. [2] [13] [14] [11] It was used as a pharmaceutical drug until 2008. [15] In 2021, its nature as a DAT allosteric modulator was reported. [8] [9] [10] As of February 2023, mesocarb was in phase 1 clinical trials for Parkinson's disease. [7] The active enantiomer, armesocarb, is also being developed. [16]

Medical uses

Mesocarb was originally developed in the Soviet Union in the 1970s [17] [18] for a variety of indications including asthenia, apathy, adynamia, and some clinical aspects of depression and schizophrenia. [19] [20] Mesocarb was used for counteracting the sedative effects of benzodiazepines, [21] increasing workload capacity and cardiovascular function, [22] treatment of attention deficit hyperactivity disorder (ADHD) in children, [23] [24] as a nootropic, [25] and as a drug to enhance resistance to extremely cold temperatures. [26] [27] It has also been reported to have antidepressant and anticonvulsant properties. [28]

Available forms

Mesocarb was sold in Russia as 5 mg oral tablets under the brand name Sydnocarb.[ citation needed ]

Pharmacology

Pharmacodynamics

Mesocarb has been found to act as a selective dopamine reuptake inhibitor (DRI) by blocking the actions of the dopamine transporter (DAT), [11] [29] and lacks the dopamine release characteristic of stimulants such as dextroamphetamine. [30] [31] [32] It was the most selective DAT inhibitor amongst an array of other DAT inhibitors to which it was compared and, in 2017, was reported as the most selective DAT inhibitor described to date. [29] [5]

The affinities (Ki) of mesocarb at the human monoamine transporters in vitro have been reported to be 8.3 nM for the dopamine transporter (DAT), 1,500 nM for the norepinephrine transporter (NET) (181-fold lower than for the DAT), and >10,000 nM for the serotonin transporter (SERT) (>1,205-fold lower than for the DAT). [5] The inhibitory potencies (IC50 Tooltip half-maximal inhibitory concentration) of mesocarb at the human monoamine transporters in vitro have been reported to be 0.49 ± 0.14 μM at the DAT, 34.9 ± 14.08 μM at the NET (71-fold lower than for the DAT), and 494.9 ± 17.00 μM at the SERT (1,010-fold lower than for the DAT). [10]

In 2021, it was discovered that mesocarb is not a conventional DRI but acts as a DAT allosteric modulator or non-competitive inhibitor. [8] [9] [10] In accordance with its nature as an atypical DAT blocker, the drug has atypical effects relative to conventional DRIs. [8] [9] [10] [5] As an example, it shows greater antiparkinsonian activity relative to other DRIs in animals. [5]

Similarly to other DRIs, mesocarb has been found to possess wakefulness-promoting effects. [5]

Pharmacokinetics

Hydroxylated metabolites can be detected in urine for up to 10 days after consumption. [33]

Mesocarb had erroneously been referred to as a prodrug of amphetamine. [34] However, this was based on older literature that relied on gas chromatography as an analytical method. Subsequently, with the advent of mass spectroscopy, it has been shown that presence of amphetamine in prior studies was an artifact of the gas chromatography method. [35] More recent studies using mass spectroscopy show that negligible levels of amphetamine are released from mesocarb metabolism. [33]

Chemistry

Mesocarb, also known as 3-(β-phenylisopropyl)-N-phenylcarbamoylsydnonimine, is a substituted phenethylamine and amphetamine and a mesoionic sydnone imine. [12] [2] [3] It has the amphetamine backbone present, except that the RN has a complicated imine side chain present. [12] [2] [3]

Whereas mesocarb (MLR-1017) is a racemic mixture, the enantiopure levorotatory or (R)-enantiomer is known as armesocarb (MLR-1019). [15] Armesocarb is described as the active enantiomer of mesocarb, whereas the (S)- or D-enantiomer is said to be virtually inactive. [5] [15] [36]

It is structurally related to feprosidnine (Sydnophen; 3-(α-methylphenylethyl)sydnone imine). [28]

Synthesis

Patents: Mesocarb synthesis.svg
Patents:

Feprosidnine (Sydnophen) is converted from the hydrochloride salt (1) into the freebase amine (2). This is then treated with phenylisocyanate (3).

History

Mesocarb was first described in the scientific literature by 1971. [2] [13] [14] [11] It is said to have been used as a pharmaceutical drug from 1971 until 2008. [15] It was said to have been discontinued by its manufacturer in 2008 for business reasons unrelated to the drug itself. [15]

Society and culture

Names

Mesocarb is the generic name of the drug and its INN Tooltip International Nonproprietary Name. [12] It is also known by the synonym fensidnimine as well as by the brand names Sydnocarb and Synocarb. [2] [3] [12] [38] The drug is additionally known by its developmental code name MLR-1017 (for Parkinson's disease). [7]

Status

Mesocarb is almost unknown in the western world and is neither used in medicine nor studied scientifically to any great extent outside of Russia and other countries in the former Soviet Union. It has however been added to the list of drugs under international control and is a scheduled substance in most countries, despite its multiple therapeutic applications and reported lack of significant abuse potential. [39]

Research

Parkinson's disease

Mesocarb, has been under development for the treatment of Parkinson's disease since 2016. [6] [7] As of February 2023, it is in phase 1 clinical trials for this indication. [7] However, no recent development has been reported. [7] Mesocarb's active enantiomer armesocarb is also under development. [16]

See also

Related Research Articles

<span class="mw-page-title-main">Amphetamine</span> Central nervous system stimulant

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity; it is also used to treat binge eating disorder in the form of its inactive prodrug lisdexamfetamine. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

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">Norepinephrine reuptake inhibitor</span> Class of drug

A norepinephrine reuptake inhibitor or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic 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">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">Feprosidnine</span> Chemical compound

Feprosidnine, sold under the brand name Sydnophen, is a stimulant drug which was developed in the USSR in the 1970s. It is structurally related to another Russian drug mesocarb but unlike mesocarb, was withdrawn earlier from production. In comparison with mesocarb it has own antidepressant activity, which makes it useful in treating depressions. Indications of feprosidnine included apathic, asthenic depressions, fatigue, apathic syndrome, narcolepsy and other similar conditions. Therapeutic range of doses: 10-50mg a day. Sydnophen has multiple mechanisms of action, the relative importance of which has not been clearly established. Effects on the body include reversible monoamine oxidase inhibition, cholinergic, adrenergic, opioid and nitric oxide donating actions, all of which may contribute to its pharmacological effects to some extent.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<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.

<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 one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; monoamine releasing agents can induce the release of one or more of these neurotransmitters.

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">3-Fluoroamphetamine</span> Stimulant drug that acts as an amphetamine

3-Fluoroamphetamine is a stimulant drug from the amphetamine family which acts as a monoamine releaser with similar potency to methamphetamine but more selectivity for dopamine and norepinephrine release over serotonin. It is self-administered by mice to a similar extent to related drugs such as 4-fluoroamphetamine and 3-methylamphetamine.

<span class="mw-page-title-main">SoRI-20041</span> Chemical compound

SoRI-20041 is an "antagonist-like" allosteric modulator of amphetamine-induced dopamine release. SoRI-20041 is believed to be the first example of a drug that separately modulates uptake versus release in the dopamine transporter ; it produces the same effects as SoRI-20040 and SoRI-9804 in uptake assays and binding assays, inhibiting the re-uptake of dopamine, but does not modulate d-amphetamine-induced DA release by inhibiting that as well, like 'agonists' of the series do.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

(<i>R</i>)-1-Aminoindan Major metabolite of rasagiline

(R)-1-Aminoindan ((R)-1-AI; developmental code name TVP-136 or TV-136), or (R)-1-aminoindane, is the major metabolite of the selective MAO-B inhibitor and antiparkinsonian agent rasagiline ((R)-N-propargyl-1-aminoindan). In contrast to rasagiline, it lacks significant monoamine oxidase inhibition. In addition, unlike selegiline and its amphetamine metabolites, it lacks monoamine reuptake-inhibiting and -releasing activities and associated amphetamine-like psychostimulant effects. However, (R)-1-aminoindan retains neuroprotective effects and certain other activities.

<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.

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.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
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  4. ↑ Froestl W, Pfeifer A, Muhs A (2013). "Cognitive enhancers (nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. disease-modifying drugs" (PDF). J Alzheimers Dis. 34 (1): 1–114. doi:10.3233/JAD-121729. PMID   23186990. MLR-1017 (mesocarb, sydnocarb, sidnocarb, Melior Pharmaceuticals, Exton, PA) (Fig. 4) is a dopamine transporter inhibitor for the potential treatment of ADHD and levodopa-induced side effects in PD. The drug was previously launched in Russia [271, 272] (Thomson Reuters Pharma, update of April 12, 2012).
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  28. 1 2 Kawase M, Sakagami H, Motohashi N (2007). "The Chemistry of Bioactive Mesoionic Heterocycles". Bioactive Heterocycles VII. Vol. 16. Berlin, Heidelberg: Springer Berlin Heidelberg. p. 135–152. doi:10.1007/7081_2007_096. ISBN   978-3-642-00335-6. Mesocarb (sydnocarb) (13) and Feprosidnine (sydnofen) (14) are stimulants developed in Russia in the 1970s. Mesocarb is sold as a drug in Russia. However, it is almost unknown in Western countries and is not used in medicine. It has been shown to act as a dopamine reuptake inhibitor, antidepressant, and anticonvulsant [7, 8].
  29. 1 2 Gruner JA, Mathiasen JR, Flood DG, Gasior M (May 2011). "Characterization of pharmacological and wake-promoting properties of the dopaminergic stimulant sydnocarb in rats". The Journal of Pharmacology and Experimental Therapeutics. 337 (2): 380–390. doi:10.1124/jpet.111.178947. PMID   21300706. S2CID   9985668.
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  31. ↑ Anderzhanova EA, Afanas'ev II, Kudrin VS, Rayevsky KS (September 2000). "Effect of d-amphetamine and sydnocarb on the extracellular level of dopamine, 3,4-dihydroxyphenylacetic acid, and hydroxyl radicals generation in rat striatum". Annals of the New York Academy of Sciences. 914 (1): 137–145. Bibcode:2000NYASA.914..137A. doi:10.1111/j.1749-6632.2000.tb05191.x. PMID   11085316. S2CID   12326076.
  32. ↑ Gainetdinov RR, Sotnikova TD, Grekhova TV, Rayevsky KS (December 1997). "Effects of a psychostimulant drug sydnocarb on rat brain dopaminergic transmission in vivo". European Journal of Pharmacology. 340 (1): 53–58. doi:10.1016/S0014-2999(97)01407-6. PMID   9527506.
  33. 1 2 Shpak AV, Appolonova SA, Semenov VA (January 2005). "Validation of liquid chromatography-electrospray ionization ion trap mass spectrometry method for the determination of mesocarb in human plasma and urine". Journal of Chromatographic Science. 43 (1): 11–21. doi: 10.1093/chromsci/43.1.11 . PMID   15808002.
  34. ↑ Dettmeyer R, Verhoff MA, Schütz HF (9 October 2013). Forensic Medicine: Fundamentals and Perspectives. Springer Science & Business Media. pp. 519–. ISBN   978-3-642-38818-7.
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  37. ↑ GB 1262830,Mashkovsky MD, Yashunsky YG, Altshuller RA, Knolodov LE, Avrutsky GY, Alexandrovsky JA, Smulevich AB,"Novel sydnonimine derivative",published 9 February 1972, assigned to Vni Khim Farmatsevtichesky II
  38. ↑ "Mesocarb". CAS Common Chemistry. American Chemical Society. 16 September 2024. CAS Registry Number 34262-84-5. Retrieved 16 September 2024.
  39. ↑ Rudenko GM, Altshuler RA (1978). "[Experimental and clinical study of Sydnocarb]". Hung Pharmacotherapy (in Russian). 124: 150–154.


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