Mesocarb

Mesocarb

Clinical data
Trade names	Sidnocarb, Sydnocarb, Synocarb
Other names	Fensidnimine; 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	BR: Class B1 (Psychoactive drugs)[1] CA: Schedule III DE: Anlage II (Authorized trade only, not prescriptible) UK: Class C US: Schedule I
Pharmacokinetic data
Metabolism	Hepatic
Excretion	Renal
Identifiers
IUPAC name 5-(Phenylcarbamoylimino)-3-(1-phenylpropan-2-yl)-5H-1,2,3-oxadiazol-3-ium-2-ide
CAS Number	34262-84-5^Y
PubChem CID	9551611
PubChem SID	497621129
ChemSpider	16736988^Y
UNII	UMT8MP2NDU
KEGG	D12716^Y
CompTox Dashboard (EPA)	DTXSID10900961
Chemical and physical data
Formula	C18H18N4O2
Molar mass	322.368 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C(\N=C1/C=[N+](\[N-]O1)C(C)Cc2ccccc2)Nc3ccccc3
InChI 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+^Y Key:DMHQLXUFCQSQQQ-LVZFUZTISA-N^Y
(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.

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 (K_i) 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 (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 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 R_N 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:[17][37]

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 INNTooltip 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

• List of Russian drugs

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.
2. 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. 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. 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).
5. Macolino-Kane CM, Ciallella JR, Lipinski CA, Reaume AG (14 July 2017). "Phenotypic Screening". Drug Repositioning (PDF). Frontiers in Neurotherapeutics. Boca Raton: CRC Press. p. 121–145. doi:10.4324/9781315373669-7. ISBN 978-1-315-37366-9.
6. "Melior Discovery Announces Spinout of Melior Pharmaceuticals II, LLC". 10 May 2016.
7. "MLR-1017 - Melior Pharmaceuticals". AdisInsight. 28 February 2023. Retrieved 16 September 2024.
8. 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.
9. 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.
10. 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.
11. 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.
12. "Mesocarb". PubChem. Retrieved 16 September 2024.
13. 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.
14. 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.
15. Adhera Therapeutics (7 June 2021). "Adhera Therapeutics Signs Letter of Intent with Melior Pharmaceuticals II to Acquire a New Class of Drug for Parkinson's Disease". GlobeNewswire News Room. Retrieved 25 September 2024. Armesocarb is the active pharmaceutical ingredient (API) of the racemic mixture mesocarb, a highly selective dopamine reuptake inhibitor first approved in the former Soviet Union in 1971 and marketed for select psychiatric and central nervous system (CNS) indications until 2008. At that time, which coincided with the Great Recession, the Russian manufacturer discontinued operations for business reasons unrelated to the compound itself.
16. "Melior Pharmaceuticals". AdisInsight. 28 April 2023. Retrieved 26 September 2024.
17. 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 
18. 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.
19. Rudenko GM, Altshuler RA (1979). "Peculiarities of clinical activity and pharmacokinetics of sydnocarb (sydnocarbum), an original psychostimulant". Agressologie. 20 (D): 265–270. PMID 45391.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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. 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.
30. 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.
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. 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.
35. 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.
36. Al'tshuler RA (2005). "Comparative Molecular Model Estimation of the Affinity of Phenylethylamines to the Binding Sites of Membrane Transporters". Pharmaceutical Chemistry Journal. 39 (4): 169–175. doi:10.1007/s11094-005-0110-3. ISSN 0091-150X.
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.