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	Atypicaldopamine 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
PubChemCID	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 nameSidnocarb orSydnocarb and known by the developmental code nameMLR-1017, is apsychostimulantmedication which has been used in the treatment ofpsychiatric disorders and for a number of other indications in theSoviet Union andRussia.^[2][3][4][5] It is currently under development for the treatment ofParkinson's disease andsleep disorders.^[6][7] It is takenby mouth.

The drug is aselectivedopamine reuptake inhibitor (DRI).^{[8][9][10][11]} It is an unusual and unique DRI, acting as anegative allosteric modulator andnon-competitive inhibitor of thedopamine transporter (DAT).^[8][9][10] Chemically, mesocarb containsamphetamine within itsstructure but has been modified and extended at theamine with asydnone imine-containingmoiety.^[12][2][3]

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

Mesocarb was originally developed in theSoviet Union in the 1970s^[17][18] for a variety of indications includingasthenia,apathy,adynamia, and some clinical aspects ofdepression andschizophrenia.^[19][20] Mesocarb was used for counteracting thesedative effects ofbenzodiazepines,^[21] increasing workload capacity andcardiovascular function,^[22] treatment ofattention deficit hyperactivity disorder (ADHD) in children,^[23][24] as anootropic,^[25] and as a drug to enhance resistance to extremely cold temperatures.^[26][27] It has also been reported to haveantidepressant andanticonvulsant properties.^[28]

Mesocarb was sold inRussia as 5 mgoraltablets under the brand name Sydnocarb.^{[citation needed]}

Mesocarb has been found to act as aselectivedopamine reuptake inhibitor (DRI) by blocking the actions of thedopamine transporter (DAT),^[11][29] and lacks thedopamine release characteristic of stimulants such asdextroamphetamine.^[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]

Theaffinities (K_i) of mesocarb at the humanmonoamine transportersin vitro have been reported to be 8.3 nM for thedopamine transporter (DAT), 1,500 nM for thenorepinephrine transporter (NET) (181-fold lower than for the DAT), and >10,000 nM for theserotonin transporter (SERT) (>1,205-fold lower than for the DAT).^[5] The inhibitorypotencies (IC₅₀Tooltip half-maximal inhibitory concentration) of mesocarb at the human monoamine transportersin 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 DATallosteric modulator ornon-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 greaterantiparkinsonian activity relative to other DRIs in animals.^[5]

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

Hydroxylatedmetabolites can be detected inurine for up to 10 days after consumption.^[33]

Mesocarb had erroneously been referred to as aprodrug ofamphetamine.^[34] However, this was based on older literature that relied ongas chromatography as ananalytical method. Subsequently, with the advent ofmass 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 mesocarbmetabolism.^[33]

Mesocarb, also known as 3-(β-phenylisopropyl)-N-phenylcarbamoylsydnonimine, is asubstituted phenethylamine andamphetamine and amesoionicsydnone imine.^[12][2][3] It has theamphetamine backbone present, except that theR_N has a complicated imineside chain present.^[12][2][3]

Whereas mesocarb (MLR-1017) is aracemic mixture, theenantiopurelevorotatory or (R)-enantiomer is known asarmesocarb (MLR-1019).^[15] Armesocarb is described as theactive enantiomer of mesocarb, whereas the (S)- orD-enantiomer is said to be virtually inactive.^[5][15][36]

It isstructurally related tofeprosidnine (Sydnophen; 3-(α-methylphenylethyl)sydnone imine).^[28]

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

Mesocarb was first described in thescientific literature by 1971.^{[2][13][14][11]} It is said to have been used as apharmaceutical 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]

Mesocarb is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name.^[12] It is also known by the synonymfensidnimine as well as by the brand namesSydnocarb andSynocarb.^{[2][3][12][38]} The drug is additionally known by its developmental code nameMLR-1017 (for Parkinson's disease).^[7]

Mesocarb is almost unknown in the western world and is neither used in medicine nor studied scientifically to any great extent outside ofRussia and other countries in the formerSoviet 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 significantabuse potential.^[39]

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

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