Esmodafinil

Esmodafinil
	(S)-(+)-Modafinil
Clinical data
Other names	CRL-40983; (S)-Modafinil; S-Modafinil; (S)-(+)-Modafinil; (+)-Modafinil; NH-02D
Drug class	Atypical dopamine reuptake inhibitor; wakefulness-promoting agent
Pharmacokinetic data
Elimination half-life	3–5 hours
Identifiers
	IUPAC name 2-[(S)-benzhydrylsulfinyl]acetamide;
CAS Number	112111-47-4;
PubChem CID	11173366;
ChemSpider	9348458;
UNII	152JRG3T0U;
ChEBI	CHEBI:77591;
ChEMBL	ChEMBL1672355;
CompTox Dashboard (EPA)	DTXSID70457709 ;
ECHA InfoCard	100.234.492
Chemical and physical data
Formula	C15H15NO2S
Molar mass	273.35 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1=CC=C(C=C1)C(C2=CC=CC=C2)[S@@](=O)CC(=O)N;
	InChI InChI=1S/C15H15NO2S/c16-14(17)11-19(18)15(12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,15H,11H2,(H2,16,17)/t19-/m0/s1; Key:YFGHCGITMMYXAQ-IBGZPJMESA-N;

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.^[3]

Esmodafinil is suspected to be less clinically useful for treating conditions that modafinil and armodafinil are marketed for, such as narcolepsy, shift work sleep disorder, and obstructive sleep apnea.^[4]

Pharmacology

Pharmacodynamics

Esmodafinil has a 3-fold lower affinity for the dopamine transporter (DAT) compared to armodafinil.^[5] Both enantiomers of modafinil preferentially bind to the DAT in an inward facing conformation that is associated with atypical dopamine reuptake inhibitor (DRI) profiles.^[5]^[6] Esmodafinil and armodafinil are said to have equipotent pharmacological effects but differing pharmacokinetics (see below).^[2]

Pharmacokinetics

Esmodafinil possesses a substantially shorter elimination half-life (3–5 hours) compared to armodafinil (10–17 hours).^[1]^[2]^[7]^[8]^[5]

Chemistry

Esmodafinil, or (S)-(+)-modafinil, is the enantiopure (S)-(+)-enantiomer of the racemic mixture modafinil, while armodafinil is the (R)-(–)-enantiomer.^[1]

A number of analogues of esmodafinil are known, including adrafinil, flmodafinil, fladrafinil, and others.^[1]

Preclinical research

Esmodafinil has been researched for the treatment of cocaine addiction.^[5]^[6] Like armodafinil, esmodafinil attenuates the effects of cocaine by occupying the dopamine transporter.^[6] While doing so, esmodafinil increases dopamine levels in the nucleus accumbens to a lesser extent than cocaine.^[5] However, the short half-life of esmodafinil has been cited as reason to investigate armodafinil as a cocaine addiction treatment instead.^[5]

Analysis in biological samples

Modafinil is considered a stimulant doping agent and as such is prohibited by World Anti-Doping Agency in sports competitions.^[9] Modafinil enantiomers can be separately quantified in biological samples.^[10]

References

^ ^a ^b ^c ^d Sousa A, Dinis-Oliveira RJ (2020). "Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects". Substance Abuse. 41 (2): 155–173. doi:10.1080/08897077.2019.1700584. PMID 31951804.
^ ^a ^b ^c Hersey M, Tanda G (2024). "Modafinil, an atypical CNS stimulant?". Pharmacological Advances in Central Nervous System Stimulants. Advances in Pharmacology. Vol. 99. pp. 287–326. doi:10.1016/bs.apha.2023.10.006. ISBN 978-0-443-21933-7. PMID 38467484.
^ "NCATS Inxight Drugs — MODAFINIL, (S)-". drugs.ncats.io. Retrieved 2023-06-28.
^ Tembe DV, Dhavale A, Desai H, Mane DN, Raut SK, Dhingra G, et al. (2011-06-01). "Armodafinil versus Modafinil in Patients of Excessive Sleepiness Associated with Shift Work Sleep Disorder: A Randomized Double Blind Multicentric Clinical Trial". Neurology Research International. 2011: 514351. doi:10.1155/2011/514351. PMC 3135062. PMID 21766023.
^ ^a ^b ^c ^d ^e ^f Loland CJ, Mereu M, Okunola OM, Cao J, Prisinzano TE, Mazier S, et al. (September 2012). "R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse". Biological Psychiatry. 72 (5): 405–413. doi:10.1016/j.biopsych.2012.03.022. PMC 3413742. PMID 22537794.
^ ^a ^b ^c Schmitt KC, Reith ME (2011). "The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors". PLOS ONE. 6 (10): e25790. Bibcode:2011PLoSO...625790S. doi:10.1371/journal.pone.0025790. PMC 3197159. PMID 22043293.
^ Niemegeers P, Maudens KE, Morrens M, Patteet L, Joos L, Neels H, et al. (September 2012). "Pharmacokinetic evaluation of armodafinil for the treatment of bipolar depression". Expert Opinion on Drug Metabolism & Toxicology. 8 (9): 1189–1197. doi:10.1517/17425255.2012.708338. PMID 22803602.
^ Garnock-Jones KP, Dhillon S, Scott LJ (September 2009). "Armodafinil". CNS Drugs. 23 (9): 793–803. doi:10.2165/11203290-000000000-00000. PMID 19689169.
^ "The Prohibited List".
^ Harvanová M, Gondová T (May 2017). "New enantioselective LC method development and validation for the assay of modafinil". Journal of Pharmaceutical and Biomedical Analysis. 138: 267–271. doi:10.1016/j.jpba.2017.02.028. PMID 28231529. S2CID 43492396.

[SousaDinis-Oliveira2020-1] Sousa A, Dinis-Oliveira RJ (2020). "Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects". Substance Abuse. 41 (2): 155–173. doi:10.1080/08897077.2019.1700584. PMID 31951804.

[HerseyTanda2024-2] Hersey M, Tanda G (2024). "Modafinil, an atypical CNS stimulant?". Pharmacological Advances in Central Nervous System Stimulants. Advances in Pharmacology. Vol. 99. pp. 287–326. doi:10.1016/bs.apha.2023.10.006. ISBN 978-0-443-21933-7. PMID 38467484.

[3] "NCATS Inxight Drugs — MODAFINIL, (S)-". drugs.ncats.io. Retrieved 2023-06-28.

[4] Tembe DV, Dhavale A, Desai H, Mane DN, Raut SK, Dhingra G, et al. (2011-06-01). "Armodafinil versus Modafinil in Patients of Excessive Sleepiness Associated with Shift Work Sleep Disorder: A Randomized Double Blind Multicentric Clinical Trial". Neurology Research International. 2011: 514351. doi:10.1155/2011/514351. PMC 3135062. PMID 21766023.

[:0-5] ^ ^a ^b ^c ^d ^e ^f Loland CJ, Mereu M, Okunola OM, Cao J, Prisinzano TE, Mazier S, et al. (September 2012). "R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse". Biological Psychiatry. 72 (5): 405–413. doi:10.1016/j.biopsych.2012.03.022. PMC 3413742. PMID 22537794.

[:1-6] Schmitt KC, Reith ME (2011). "The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors". PLOS ONE. 6 (10): e25790. Bibcode:2011PLoSO...625790S. doi:10.1371/journal.pone.0025790. PMC 3197159. PMID 22043293.

[NiemegeersMaudensMorrens2012-7] Niemegeers P, Maudens KE, Morrens M, Patteet L, Joos L, Neels H, et al. (September 2012). "Pharmacokinetic evaluation of armodafinil for the treatment of bipolar depression". Expert Opinion on Drug Metabolism & Toxicology. 8 (9): 1189–1197. doi:10.1517/17425255.2012.708338. PMID 22803602.

[Garnock-JonesDhillonScott2009-8] Garnock-Jones KP, Dhillon S, Scott LJ (September 2009). "Armodafinil". CNS Drugs. 23 (9): 793–803. doi:10.2165/11203290-000000000-00000. PMID 19689169.

[9] "The Prohibited List".

[pmid28231529-10] Harvanová M, Gondová T (May 2017). "New enantioselective LC method development and validation for the assay of modafinil". Journal of Pharmaceutical and Biomedical Analysis. 138: 267–271. doi:10.1016/j.jpba.2017.02.028. PMID 28231529. S2CID 43492396.

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