Chemistry:Methylephedrine

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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.[1][2][3] It is reported to be used in various over-the-counter cough and cold preparations throughout the world, including Japan.[3]

The drug is an ephedrine-like sympathomimetic and activates α- and β-adrenergic receptors.[4] Chemically, it is a substituted amphetamine and is closely related to ephedrine.[1][2]

Methylephedrine was discovered by 1927.[5] It is mostly no longer marketed as a prescription drug.[2] The drug is also found naturally as an alkaloid in Ephedra species including Ephedra sinica, Ephedra vulgaris, and Ephedra distachya.[1][5]

Side effects

Rarely, heart failure and stroke in association with use of methylephedrine have been reported.[6][7][8]

Methylephedrine shows reinforcing effects, a measure of addiction and misuse potential, in monkeys.[9]

Pharmacology

Pharmacodynamics

Methylephedrine is a sympathomimetic and ephedrine-like agent.[4][3] Ephedrine and related agents act as norepinephrine releasing agents and hence as indirectly acting sympathomimetics.[3] In relation to this, methylephedrine stimulates α- and β-adrenergic receptors.[4][3] The drug has bronchodilator and nasal decongestant effects.[4]

The occupancy of the dopamine transporter (DAT) by racemic methylephedrine has been studied.[10]

Pharmacokinetics

Methylephedrine is metabolized into ephedrine and norephedrine.[3][11] It is excreted in urine 33 to 40% unchanged, 15% as methylephedrine N-oxide, and 8% as ephedrine after 24 hours.[3][11]

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.[1][2] It is the N-methylated derivative of ephedrine ((1R,2S)-β-hydroxy-N-methylamphetamine).[1][2]

A closely related compound and stereoisomer of methylephedrine is N-methylpseudoephedrine.[1] Another related analogue is dimethylamphetamine (N,N-dimethylamphetamine), which is said to be a prodrug of methamphetamine and/or amphetamine.[12] Other analogues include etafedrine (N-ethylephedrine) and cinnamedrine (N-cinnamylephedrine).[1]

The experimental log P of methylephedrine is 2.47 and its predicted log P ranges from 1.7 to 1.74.[13][3][14]

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.[15]

History

Methylephedrine was discovered via isolation from Ephedra by 1927.[5]

Society and culture

Names

Methylephedrine is the generic name of the drug and its BAN.[1][2][16] In the case of the hydrochloride salt, its generic name is methylephedrine hydrochloride and this is its BANM.[1][2][16] Brand names of methylephedrine include Metheph, Methy-F, and Tybraine, among others.[1][2][16]

Recreational use

Similarly to ephedrine, methylephedrine may have misuse potential.[3][17] The drug shows reinforcing effects in monkeys.[9] It is one of the four constituents of BRON, a Japanese over-the-counter cough medicine with reports of misuse.[3][17] However, addiction liability of BRON was attributed primarily to the codeine component.[17] A case report of addiction to methylephedrine exists.[8]

Use in sports and exercise

Methylephedrine is on the World Anti-Doping Agency's prohibited list.[4]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. 2014. p. 435. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA435. Retrieved 2024-09-01. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 783. ISBN 978-3-88763-101-7. https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA783. Retrieved 1 September 2024. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 "DL-Methylephedrine: Uses, Interactions, Mechanism of Action". 22 November 2018. https://go.drugbank.com/drugs/DB11278. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". British Journal of Pharmacology 154 (3): 606–622. June 2008. doi:10.1038/bjp.2008.124. PMID 18500382. 
  5. ↑ 5.0 5.1 5.2 "CCLXX. l-Methylephedrine, an alkaloid from Ephedra species". J. Chem. Soc.: 2056–2059. 1927. doi:10.1039/jr9270002056. 
  6. ↑ "Methylephedrine-induced heart failure in a habitual user of paediatric cough syrup: a case report". European Heart Journal: Case Reports 4 (3): 1–4. June 2020. doi:10.1093/ehjcr/ytaa095. PMID 32617471. 
  7. ↑ "Ischemic stroke associated with cough and cold preparation containing methylephedrine and supplement containing Chinese herbal drugs". Internal Medicine 49 (4): 335–338. 2010. doi:10.2169/internalmedicine.49.2704. PMID 20154441. 
  8. ↑ 8.0 8.1 "[Ischemic stroke in a young patient with methylephedrine addiction: a case report]" (in Japanese). Rinsho Shinkeigaku = Clinical Neurology 46 (4): 274–277. April 2006. PMID 16768095. 
  9. ↑ 9.0 9.1 "[Studies on reinforcing effects of methylephedrine, caffeine and their mixture with intravenous-self administration in rhesus monkeys]" (in Japanese). Eisei Shikenjo Hokoku. Bulletin of National Institute of Hygienic Sciences (110): 15–22. 1992. PMID 1364430. 
  10. ↑ "Effect of DL-Methylephedrine on Dopamine Transporter Using Positron Emission Tomography With [18FFE-PE2I"]. Frontiers in Psychiatry 13. 2022. doi:10.3389/fpsyt.2022.799319. PMID 35711596. 
  11. ↑ 11.0 11.1 Cite error: Invalid <ref> tag; no text was provided for refs named InoueSuzuki1990
  12. ↑ Forensic Medicine: Fundamentals and Perspectives. Springer Science & Business Media. 9 October 2013. pp. 519–. ISBN 978-3-642-38818-7. https://books.google.com/books?id=yHHABAAAQBAJ&pg=PA519. 
  13. ↑ "(1R,2S)-2-(dimethylamino)-1-phenylpropan-1-ol". https://pubchem.ncbi.nlm.nih.gov/compound/64782. 
  14. ↑ "(−)-N-Methylephedrine". 2024-09-01. https://www.chemspider.com/Chemical-Structure.58315.html. 
  15. ↑ (1R,2S)-(−)-N-Methylephedrine at Sigma-Aldrich
  16. ↑ 16.0 16.1 16.2 Schweizerischer Apotheker-Verein (2000). Index Nominum 2000: International Drug Directory. Medpharm Scientific Publishers. p. 672. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA672. Retrieved 1 September 2024. 
  17. ↑ 17.0 17.1 17.2 "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. 1991-01-01. doi:10.1016/0278-5846(91)90026-W. PMID 1749828. 



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