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Methylephedrine

Clinical data
Trade names	Metheph, Methy-F, Tybraine
Other names	N-Methylephedrine; N-Methyl-(–)-ephedrine; L-Methylephedrine; N-Methyl-L-ephedrine; (−)-N-Methylephedrine; N,N-Dimethylnorephedrine
Drug class	Sympathomimetic; Norepinephrine releasing agent; Bronchodilator; Nasal decongestant; Antitussive
Pharmacokinetic data
Metabolites	• Methylephedrine N-oxide • Ephedrine • Norephedrine
Excretion	Urine
Identifiers
IUPAC name (1R,2S)-2-(dimethylamino)-1-phenylpropan-1-ol
CAS Number	552-79-4
PubChem CID	64782
DrugBank	DB11278
ChemSpider	58315
UNII	SHS9PGQ2LS
KEGG	D08206
ChEBI	CHEBI:113556
ChEMBL	ChEMBL445001
CompTox Dashboard (EPA)	DTXSID7045992
ECHA InfoCard	100.008.203
Chemical and physical data
Formula	C11H17NO
Molar mass	179.263 g·mol
3D model (JSmol)	Interactive image
SMILES C((C1=CC=CC=C1)O)N(C)C
InChI InChI=1S/C11H17NO/c1-9(12(2)3)11(13)10-7-5-4-6-8-10/h4-9,11,13H,1-3H3/t9-,11-/m0/s1 Key:FMCGSUUBYTWNDP-ONGXEEELSA-N

Methylephedrine, sold under the brand name Metheph among others, is a sympathomimetic medication described as an antiasthmatic agent and used to treat coughing and nasal congestion. It is reported to be used in various over-the-counter cough and cold preparations throughout the world, including Japan.

The drug is an ephedrine-like sympathomimetic and activates α- and β-adrenergic receptors. Chemically, it is a substituted amphetamine and is closely related to ephedrine.

Methylephedrine was discovered by 1927. It is mostly no longer marketed as a prescription drug. The drug is also found naturally as an alkaloid in Ephedra species including Ephedra sinica, Ephedra vulgaris, and Ephedra distachya.

Side effects

Rarely, heart failure and stroke in association with use of methylephedrine have been reported.

Methylephedrine shows reinforcing effects, a measure of addiction and misuse potential, in monkeys.

Pharmacology

Pharmacodynamics

Methylephedrine is a sympathomimetic and ephedrine-like agent. Ephedrine and related agents act as norepinephrine releasing agents and hence as indirectly acting sympathomimetics. In relation to this, methylephedrine stimulates α- and β-adrenergic receptors. The drug has bronchodilator and nasal decongestant effects.

The occupancy of the dopamine transporter (DAT) by racemic methylephedrine has been studied.

Pharmacokinetics

Methylephedrine is metabolized into ephedrine and norephedrine. It is excreted in urine 33 to 40% unchanged, 15% as methylephedrine N-oxide, and 8% as ephedrine after 24 hours.

Chemistry

Methylephedrine, also known as (1R,2S)-β-hydroxy-N,N-dimethyl-α-methyl-β-phenethylamine and as (1R,2S)-β-hydroxy-N,N-dimethylamphetamine, is a substituted phenethylamine and amphetamine derivative. It is the N-methylated derivative of ephedrine ((1R,2S)-β-hydroxy-N-methylamphetamine).

A closely related compound and stereoisomer of methylephedrine is N-methylpseudoephedrine. Another related analogue is dimethylamphetamine (N,N-dimethylamphetamine), which is said to be a prodrug of methamphetamine and/or amphetamine. Other analogues include etafedrine (N-ethylephedrine) and cinnamedrine (N-cinnamylephedrine).

The experimental log P of methylephedrine is 2.47 and its predicted log P ranges from 1.7 to 1.74.

In organic chemistry, N-methylephedrine is used as a resolving agent and as a precursor to chiral supporting electrolytes, phase-transfer catalysts, and reducing agents.

History

Methylephedrine was discovered via isolation from Ephedra by 1927.

Society and culture

Names

Methylephedrine is the generic name of the drug and its BANTooltip British Approved Name. In the case of the hydrochloride salt, its generic name is methylephedrine hydrochloride and this is its BANMTooltip British Approved Name. Brand names of methylephedrine include Metheph, Methy-F, and Tybraine, among others.

Recreational use

Similarly to ephedrine, methylephedrine may have misuse potential. The drug shows reinforcing effects in monkeys. It is one of the four constituents of BRON, a Japanese over-the-counter cough medicine with reports of misuse. However, addiction liability of BRON was attributed primarily to the codeine component. A case report of addiction to methylephedrine exists.

Use in sports and exercise

Methylephedrine is on the World Anti-Doping Agency's prohibited list.

References

1. ^ "DL-Methylephedrine: Uses, Interactions, Mechanism of Action". DrugBank Online. 22 November 2018. Retrieved 1 September 2024.
2. ^ Inoue T, Suzuki S (January 1990). "The metabolism of (+-)-methylephedrine in rat and man". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 20 (1): 99–106. doi:10.3109/00498259009046816. PMID 2327112.
3. ^ Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 435. ISBN 978-1-4757-2085-3. Retrieved 2024-09-01.
4. ^ Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 783. ISBN 978-3-88763-101-7. Retrieved 1 September 2024.
5. ^ Docherty JR (June 2008). "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". British Journal of Pharmacology. 154 (3): 606–622. doi:10.1038/bjp.2008.124. PMC 2439527. PMID 18500382.
6. ^ Smith (1927). "CCLXX. l-Methylephedrine, an alkaloid from Ephedra species". J. Chem. Soc.: 2056–2059. doi:10.1039/jr9270002056.
7. Suzuki M, Higashi H, Ikeda S, Yamaguchi O (June 2020). "Methylephedrine-induced heart failure in a habitual user of paediatric cough syrup: a case report". European Heart Journal: Case Reports. 4 (3): 1–4. doi:10.1093/ehjcr/ytaa095. PMC 7319816. PMID 32617471.
8. Imai N, Yagi N, Konishi T, Serizawa M, Kobari M (2010). "Ischemic stroke associated with cough and cold preparation containing methylephedrine and supplement containing Chinese herbal drugs". Internal Medicine. 49 (4): 335–338. doi:10.2169/internalmedicine.49.2704. PMID 20154441.
9. ^ Kunieda T, Imai K, Mori T, Izumoto H, Takabatake N, Yamamoto S (April 2006). "". Rinsho Shinkeigaku = Clinical Neurology (in Japanese). 46 (4): 274–277. PMID 16768095.
10. ^ Sekita K, Ochiai T, Ohno K, Murakami O, Wakasa Y, Uzawa K, et al. (1992). "". Eisei Shikenjo Hokoku. Bulletin of National Institute of Hygienic Sciences (in Japanese) (110): 15–22. PMID 1364430.
11. Nogami T, Arakawa R, Sakayori T, Ikeda Y, Okubo Y, Tateno A (2022). "Effect of DL-Methylephedrine on Dopamine Transporter Using Positron Emission Tomography With [F]FE-PE2I". Frontiers in Psychiatry. 13: 799319. doi:10.3389/fpsyt.2022.799319. PMC 9193582. PMID 35711596.
12. 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.
13. "(1R,2S)-2-(dimethylamino)-1-phenylpropan-1-ol". PubChem. Retrieved 1 September 2024.
14. "(−)-N-Methylephedrine". ChemSpider. 2024-09-01. Retrieved 2024-09-01.
15. (1R,2S)-(−)-N-Methylephedrine at Sigma-Aldrich
16. ^ Schweizerischer Apotheker-Verein (2000). Index Nominum 2000: International Drug Directory. Medpharm Scientific Publishers. p. 672. ISBN 978-3-88763-075-1. Retrieved 1 September 2024.
17. ^ Ishigooka J, Yoshida Y, Murasaki M (1991-01-01). "Abuse of "BRON": a Japanese OTC cough suppressant solution containing methylephedrine, codeine, caffeine and chlorpheniramine". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 15 (4): 513–521. doi:10.1016/0278-5846(91)90026-W. PMID 1749828. S2CID 53187238.

• Amphetamine alkaloids
• Beta-Hydroxyamphetamines
• Bronchodilators
• Dimethylamino compounds
• Drugs in sport
• Enantiopure drugs
• Ergogenic aids
• Methamphetamines
• Norepinephrine releasing agents
• Stimulants
• Sympathomimetics