Methylephedrine

Methylephedrine
Clinical data
Trade namesMetheph, Methy-F, Tybraine
Other namesN-Methylephedrine; N-Methyl-(–)-ephedrine; L-Methylephedrine; N-Methyl-L-ephedrine; (−)-N-Methylephedrine; N,N-Dimethylnorephedrine
Drug classSympathomimetic; Norepinephrine releasing agent; Bronchodilator; Nasal decongestant; Antitussive
Pharmacokinetic data
Metabolites• Methylephedrine N-oxide[1][2]
• Ephedrine[1][2]
• Norephedrine[1][2]
ExcretionUrine[1]
Identifiers
IUPAC name
  • (1R,2S)-2-(dimethylamino)-1-phenylpropan-1-ol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.008.203
Chemical and physical data
FormulaC11H17NO
Molar mass179.263 g·mol−1
3D model (JSmol)
SMILES
  • C[C@@H]([C@@H](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.[3][4][1] It is reported to be used in various over-the-counter cough and cold preparations throughout the world, including Japan.[1]

The drug is an ephedrine-like sympathomimetic and activates α- and β-adrenergic receptors.[5] Chemically, it is a substituted amphetamine and is closely related to ephedrine.[3][4]

Methylephedrine was discovered by 1927.[6] It is mostly no longer marketed as a prescription drug.[4] The drug is also found naturally as an alkaloid in Ephedra species including Ephedra sinica, Ephedra vulgaris, and Ephedra distachya.[3][6]

Side effects

Rarely, heart failure and stroke in association with use of methylephedrine have been reported.[7][8][9]

Methylephedrine shows reinforcing effects, a measure of addiction and misuse potential, in monkeys.[10]

Pharmacology

Pharmacodynamics

Methylephedrine is a sympathomimetic and ephedrine-like agent.[5][1] Ephedrine and related agents act as norepinephrine releasing agents and hence as indirectly acting sympathomimetics.[1] In relation to this, methylephedrine stimulates α- and β-adrenergic receptors.[5][1] The drug has bronchodilator and nasal decongestant effects.[5]

The occupancy of the dopamine transporter (DAT) by racemic methylephedrine has been studied.[11]

Pharmacokinetics

Methylephedrine is metabolized into ephedrine and norephedrine.[1][2] It is excreted in urine 33 to 40% unchanged, 15% as methylephedrine N-oxide, and 8% as ephedrine after 24 hours.[1][2]

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.[3][4] It is the N-methylated derivative of ephedrine ((1R,2S)-β-hydroxy-N-methylamphetamine).[3][4]

A closely related compound and stereoisomer of methylephedrine is N-methylpseudoephedrine.[3] 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).[3]

The experimental log P of methylephedrine is 2.47 and its predicted log P ranges from 1.7 to 1.74.[13][1][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.[6]

Society and culture

Names

Methylephedrine is the generic name of the drug and its BANTooltip British Approved Name.[3][4][16] In the case of the hydrochloride salt, its generic name is methylephedrine hydrochloride and this is its BANMTooltip British Approved Name.[3][4][16] Brand names of methylephedrine include Metheph, Methy-F, and Tybraine, among others.[3][4][16]

Recreational use

Similarly to ephedrine, methylephedrine may have misuse potential.[1][17] The drug shows reinforcing effects in monkeys.[10] It is one of the four constituents of BRON, a Japanese over-the-counter cough medicine with reports of misuse.[1][17] However, addiction liability of BRON was attributed primarily to the codeine component.[17] A case report of addiction to methylephedrine exists.[9]

Use in sports and exercise

Methylephedrine is on the World Anti-Doping Agency's prohibited list.[5]

References

  1. ^ a b c d e f g h i j k l m n "DL-Methylephedrine: Uses, Interactions, Mechanism of Action". DrugBank Online. 22 November 2018. Retrieved 1 September 2024.
  2. ^ a b c d e 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. ^ a b c d e f g h i j 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. ^ a b c d e f g h 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. ^ a b c d e 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. ^ a b c 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. ^ a b Kunieda T, Imai K, Mori T, Izumoto H, Takabatake N, Yamamoto S (April 2006). "[Ischemic stroke in a young patient with methylephedrine addiction: a case report]". Rinsho Shinkeigaku = Clinical Neurology (in Japanese). 46 (4): 274–277. PMID 16768095.
  10. ^ a b Sekita K, Ochiai T, Ohno K, Murakami O, Wakasa Y, Uzawa K, et al. (1992). "[Studies on reinforcing effects of methylephedrine, caffeine and their mixture with intravenous-self administration in rhesus monkeys]". 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 [18F]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. ^ a b c 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. ^ a b c 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.
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