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Mesocarb

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Mesocarb
Clinical data
Trade namesSidnocarb, Sydnocarb, Synocarb
Other namesFensidnimine; Pharmaneocarb; Sydnocarbum; N-Phenylcarbamoyl-3-(β-phenylisopropyl)sydnonimine; 3-(β-Phenylisopropyl)-N-phenylcarbamoylsydnonimine; Armesocarb; MLR-1019
Routes of
administration		Oral
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic
ExcretionRenal
Identifiers
  • 5-(Phenylcarbamoylimino)-3-(1-phenylpropan-2-yl)-5H-1,2,3-oxadiazol-3-ium-2-ide
CAS Number
PubChem CID
PubChem SID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC18H18N4O2
Molar mass322.368 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+ checkY
  • Key:DMHQLXUFCQSQQQ-LVZFUZTISA-N checkY
  (verify)

Mesocarb, sold under the brand name Sidnocarb or Sydnocarb and known by the developmental code name MLR-1019, 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] It is currently under development for the treatment of Parkinson's disease and sleep disorders.[4][5] It is taken by mouth.

The drug is a selective dopamine reuptake inhibitor (DRI).[6][7][8][9] It is an unusual and unique DRI, acting as a negative allosteric modulator and non-competitive inhibitor of the dopamine transporter (DAT).[6][7][8] Chemically, mesocarb contains amphetamine within its structure but has been modified and extended at the amine with a sydnone imine-containing moiety.[10][2][3]

Mesocarb was first described by 1971.[2][11][12][9] In 2021, its nature as a DAT allosteric modulator was reported.[6][7][8] As of April 2023, mesocarb is in phase 1 clinical trials for Parkinson's disease and in the preclinical stage of development for sleep disorders.[5]

Medical uses

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Mesocarb was originally developed in the Soviet Union in the 1970s[13][14] for a variety of indications including asthenia, apathy, adynamia, and some clinical aspects of depression and schizophrenia.[15][16] Mesocarb was used for counteracting the sedative effects of benzodiazepines,[17] increasing workload capacity and cardiovascular function,[18] treatment of attention deficit hyperactivity disorder (ADHD) in children,[19][20] as a nootropic,[21] and as a drug to enhance resistance to extremely cold temperatures.[22][23] It has also been reported to have antidepressant and anticonvulsant properties.[24]

Available forms

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

Pharmacology

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Pharmacodynamics

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Mesocarb has been found to act as a selective dopamine reuptake inhibitor (DRI) by blocking the actions of the dopamine transporter (DAT),[9][25] and lacks the dopamine release characteristic of stimulants such as dextroamphetamine.[26][27][28] It was the most selective DAT inhibitor amongst an array of other DAT inhibitors to which it was compared.[25]

The inhibitory potencies (IC50Tooltip 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 norepinephrine transporter (NET) (71-fold lower), and 494.9 ± 17.00 µM at the serotonin transporter (1,010-fold lower).[8]

In 2021, it was discovered that mesocarb is not a conventional DRI but acts as a DAT allosteric modulator or non-competitive inhibitor and has atypical effects relative to conventional DRIs.[6][7][8]

Pharmacokinetics

[edit]

Hydroxylated metabolites can be detected in urine for up to 10 days after consumption.[29]

Mesocarb had erroneously been referred to as a prodrug of amphetamine.[30] 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.[31] More recent studies using mass spectroscopy show that negligible levels of amphetamine are released from mesocarb metabolism.[29]

Chemistry

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Mesocarb, also known as 3-(β-phenylisopropyl)-N-phenylcarbamoylsydnonimine, is a substituted phenethylamine and amphetamine and a mesoionic sydnone imine.[10][2][3] It has the amphetamine backbone present, except that the RN has a complicated imine side chain present.[10][2][3]

It is structurally related to feprosidnine (Sydnophen; 3-(α-methylphenylethyl)sydnone imine).[24]

Synthesis

[edit]
Patents:[13][32]

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

History

[edit]

Mesocarb was first described in the scientific literature by 1971.[2][11][12][9]

Society and culture

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Names

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Mesocarb is the generic name of the drug and its INNTooltip International Nonproprietary Name.[10] It is also known by the synonym fensidnimine as well as by the brand names Sydnocarb and Synocarb.[2][3][10][33] The drug is additionally known by its developmental code name MLR-1019 (for Parkinson's disease and other indications).[5]

Status

[edit]

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.[34]

Research

[edit]

Parkinson's disease

[edit]

Mesocarb has been under development for the treatment of Parkinson's disease since 2016.[4][5] As of April 2023, it is in phase 1 clinical trials for this indication.[5] A phase 2 trial is being planned.[5] It is also in the preclinal stage of development for sleep disorders.[5] It was previously approved for treatment of psychiatric disorders, but it was withdrawn from the market.[5]

References

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  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.
  2. ^ a b c d e f g Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 774. ISBN 978-1-4757-2085-3. Retrieved 16 September 2024.
  3. ^ a b c d e Schweizerischer Apotheker-Verein (2000). Index Nominum 2000: International Drug Directory. Index nominum. Medpharm Scientific Publishers. p. 655. ISBN 978-3-88763-075-1. Retrieved 16 September 2024.
  4. ^ a b "Melior Discovery Announces Spinout of Melior Pharmaceuticals II, LLC". 10 May 2016.
  5. ^ a b c d e f g h "Melior Pharmaceuticals". AdisInsight. 28 April 2023. Retrieved 16 September 2024.
  6. ^ a b c d Nepal B, Das S, Reith ME, Kortagere S (2023). "Overview of the structure and function of the dopamine transporter and its protein interactions". Front Physiol. 14: 1150355. doi:10.3389/fphys.2023.1150355. PMC 10020207. PMID 36935752.
  7. ^ a b c d Nguyen H, Cheng MH, Lee JY, Aggarwal S, Mortensen OV, Bahar I (2024). "Allosteric modulation of serotonin and dopamine transporters: New insights from computations and experiments". Curr Res Physiol. 7: 100125. doi:10.1016/j.crphys.2024.100125. PMC 11148570. PMID 38836245.
  8. ^ a b c d e Aggarwal S, Cheng MH, Salvino JM, Bahar I, Mortensen OV (June 2021). "Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb as an Allosteric Modulator of the Human Dopamine Transporter". Biomedicines. 9 (6): 634. doi:10.3390/biomedicines9060634. PMC 8227285. PMID 34199621.
  9. ^ a b c d Erdö SL, Kiss B, Rosdy B (1981). "Inhibition of dopamine uptake by a new psychostimulant mesocarb (Sydnocarb)". Pol J Pharmacol Pharm. 33 (2): 141–147. PMID 7312716.
  10. ^ a b c d e "Mesocarb". PubChem. Retrieved 16 September 2024.
  11. ^ a b Anokhina IP, Zabrodin GD, Svirinovskiĭ IE (1974). "Osobennosti mekhanizma tsentral'nogo deĭstviia sidnokarba" [Characteristics of the central action of sidnocarb]. Zh Nevropatol Psikhiatr Im S S Korsakova (in Russian). 74 (4): 594–602. PMID 4825943.
  12. ^ a b Polgár M, Vereczkey L, Czira G, Tamás J, Szporny L (1978). "Sydnocarb metabolizmusának vizsgálata pathányban" [Synocarb metabolism in rats]. Acta Pharm Hung (in Hungarian). 48 Suppl: 23–24. PMID 749521.
  13. ^ a b DE 2028880, Mashkovskii ME, Yashunskii VG, Altshuler RA, Kholodov LE, Avrutskii GY, Aleksandrovskii YA, Shmulevich AB, "N-(Phenylcarbamoyl)-3-(1-phenyl-2-propyl)sydnone imine", issued 8 March 1979, assigned to Ordzhonikidze, S., All-Union Scientific-Research Chemical-Pharmaceutical Institute 
  14. ^ Anokhina IP, Zabrodin GD, Svirinovskiĭ I (1974). "[Characteristics of the central action of sidnocarb]" [Characteristics of the central action of sidnocarb]. Zhurnal Nevropatologii I Psikhiatrii imeni S.S. Korsakova (in Russian). 74 (4): 594–602. PMID 4825943.
  15. ^ Rudenko GM, Altshuler RA (1979). "Peculiarities of clinical activity and pharmacokinetics of sydnocarb (sydnocarbum), an original psychostimulant". Agressologie. 20 (D): 265–270. PMID 45391.
  16. ^ Witkin JM, Savtchenko N, Mashkovsky M, Beekman M, Munzar P, Gasior M, et al. (March 1999). "Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: comparisons with methamphetamine". The Journal of Pharmacology and Experimental Therapeutics. 288 (3): 1298–1310. PMID 10027871.
  17. ^ Valueva LN, Tozhanova NM (1982). "[Sidnocarb correction of the adverse effects of benzodiazepine tranquilizers]" [Sidnocarb correction of the adverse effects of benzodiazepine tranquilizers]. Zhurnal Nevropatologii I Psikhiatrii imeni S.S. Korsakova (in Russian). 82 (8): 92–97. PMID 6127851.
  18. ^ Vinar O, Klein DF, Potter WZ, Gause EM (December 1991). "A survey of psychotropic medications not available in the United States". Neuropsychopharmacology. 5 (4): 201–217. PMID 1804161.
  19. ^ Turova NF, Misionzhnik EI, Ermolina LA, Aziavchik AV, Krasov VA (1988). "[Excretion of monoamines, their precursors and metabolites in the hyperactivity syndrome in mentally defective children]" [Excretion of monoamines, their precursors and metabolites in the hyperactivity syndrome in mentally defective children]. Voprosy Meditsinskoi Khimii (in Russian). 34 (1): 47–50. PMID 3369126.
  20. ^ Krasov VA (1988). "[Sidnocarb treatment of young schoolchildren with the hyperdynamic syndrome]" [Sidnocarb treatment of young schoolchildren with the hyperdynamic syndrome]. Zhurnal Nevropatologii I Psikhiatrii imeni S.S. Korsakova (in Russian). 88 (8): 97–101. PMID 3195293.
  21. ^ Ganiev MM, Kharlamov AN, Raevskiĭ KS, Guseĭnov DI (October 1987). "[Effect of sidnocarb on learning and memory]" [Effect of sidnocarb on learning and memory]. Biulleten' Eksperimental'noi Biologii I Meditsiny (in Russian). 104 (10): 453–454. PMID 3676468.
  22. ^ Barer AS, Lakota NG, Ostrovskaia GZ, Shashkov VS (Nov–Dec 1988). "[Pharmacologic correction of the effect of cold on man]" [Pharmacologic correction of the effect of cold on man]. Kosmicheskaia Biologiia I Aviakosmicheskaia Meditsina (in Russian). 22 (6): 66–73. PMID 2906380.
  23. ^ Levina MN, Badyshtov BA, Gan'shina TS (2006). "[Thermoprotector properties of a combination of sydnocarb with ladasten]" [Thermoprotector properties of a combination of sydnocarb with ladasten]. Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 69 (1): 71–73. PMID 16579065.
  24. ^ a b 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].
  25. ^ a b 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.
  26. ^ Afanas'ev II, Anderzhanova EA, Kudrin VS, Rayevsky KS (2001). "Effects of amphetamine and sydnocarb on dopamine release and free radical generation in rat striatum". Pharmacology, Biochemistry, and Behavior. 69 (3–4): 653–658. doi:10.1016/S0091-3057(01)00574-3. PMID 11509228. S2CID 32739707.
  27. ^ 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.
  28. ^ 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.
  29. ^ a b 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.
  30. ^ 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.
  31. ^ Appolonova SA, Shpak AV, Semenov VA (February 2004). "Liquid chromatography-electrospray ionization ion trap mass spectrometry for analysis of mesocarb and its metabolites in human urine". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 800 (1–2): 281–289. doi:10.1016/j.jchromb.2003.10.071. PMID 14698267.
  32. ^ 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 
  33. ^ "Mesocarb". CAS Common Chemistry. American Chemical Society. 16 September 2024. CAS Registry Number 34262-84-5. Retrieved 16 September 2024.
  34. ^ Rudenko GM, Altshuler RA (1978). "[Experimental and clinical study of Sydnocarb]". Hung Pharmacotherapy (in Russian). 124: 150–154.


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