Chemistry:Levomethadone

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Levomethadone, sold under the brand name L-Polamidon among others, is a synthetic opioid analgesic and antitussive which is marketed in Europe and is used for pain management and in opioid maintenance therapy.[1][2][3] In addition to being used as a pharmaceutical drug itself, levomethadone is also the main therapeutic component of methadone, which is a racemic mixture of levomethadone (R-methadone) and dextromethadone (S-methadone).[2][4]

Levomethadone is used for narcotic maintenance in place of, or in some cases alongside as an alternative, to racemic methadone,[5] owing to concern that the cardiotoxic and QT-prolonging action of racemic methadone might be primarily caused by dextromethadone.[6][5]

Pharmacology

Pharmacodynamics

Levomethadone has approximately 50x the potency of the S-(+)-enantiomer as well as greater μ-opioid receptor selectivity.[1][7] Accordingly, it is about twice as potent as methadone by weight and its effects are virtually identical in comparison.[8][9] In addition to its activity at the opioid receptors, levomethadone has been found to act as a weak competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor complex[10] and as a potent noncompetitive antagonist of the α3β4 nicotinic acetylcholine (nACh) receptor.[11]

v · d · e Methadone at opioid receptors, monoamine transporters, and the NMDA receptor
Compound Affinities (Ki) Ratios
MOR DOR KOR SERT NET NMDAR MOR:DOR:KOR SERT:NET
Methadone 1.7 nM 435 nM 405 nM ND ND 2,500–8,300 nM 1:256:238 ND
  Dextromethadone 19.7 nM 960 nM 1,370 nM 992 nM 12,700 nM 2,600–7,400 nM 1:49:70 1:13
  Levomethadone 0.945 nM 371 nM 1,860 nM 14.1 nM 702 nM 2,800–3,400 nM 1:393:1968 1:50
Sources: See template.

Chemistry

The separation of the stereoisomers is one of the easier in organic chemistry and is described in the original patent.[12] It involves "treatment of racemic methadone base with d-(+)-tartaric acid in an acetone/water mixture [which] precipitates almost solely the dextro-methadone levo-tartrate, and the more potent Levomethadone can easily be retrieved from the mother liquor in a high state of optical purity."[13]

There is now an asymmetric synthesis[14] available to prepare both levomethadone (R-(−)-methadone) and dextromethadone (S-(+)-methadone).[15]

Society and culture

Generic names

Levomethadone is the generic name of the drug and its INN.[3][2]

Brand names

Levomethadone has been sold under brand names including L-Polaflux, L-Polamidon, L-Polamivet, Levadone, Levo-Methasan, Levothyl, Mevodict, Levopidon and Vistadict, among others.[16][3][2]

Levomethadone is listed under the Single Convention On Narcotic Drugs 1961 and is a Schedule II Narcotic controlled substance in the US as an isomer of methadone (ACSCN 9250) and is not listed separately, nor is dextromethadone.[17] It is similarly controlled under the German Betäubungsmittelgesetz and similar laws in practically every other country.[18][19]

References

  1. ↑ 1.0 1.1 Cite error: Invalid <ref> tag; no text was provided for refs named Buschmann2002
  2. ↑ 2.0 2.1 2.2 2.3 Dictionary of Pharmacological Agents. CRC Press. 1997. p. 1294. ISBN 978-0-412-46630-4. https://books.google.com/books?id=A0THacd46ZsC&pg=PA1294. Retrieved 17 May 2012. 
  3. ↑ 3.0 3.1 3.2 Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 605. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA605. Retrieved 17 May 2012. 
  4. ↑ PubChem. "Methadone" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/4095. 
  5. ↑ 5.0 5.1 "Side effects of levomethadone and racemic methadone in a maintenance program". Clinical Pharmacology and Therapeutics 20 (4): 445–449. October 1976. doi:10.1002/cpt1976204445. PMID 788990. 
  6. ↑ "Stereoselective Block of hERG Channel by (S)-Methadone and QT Interval Prolongation in CYP2B6 Slow Metabolizers". Clinical Pharmacology and Therapeutics 81 (5): 719–728. May 2007. doi:10.1038/sj.clpt.6100120. PMID 17329992. 
  7. ↑ Surface Design: Applications in Bioscience and Nanotechnology. Wiley-VCH. 11 August 2009. p. 193. ISBN 978-3-527-40789-7. https://books.google.com/books?id=J0fhTBYVJioC&pg=PA193. Retrieved 17 May 2012. 
  8. ↑ Oxford American Handbook of Hospice and Palliative Medicine. Oxford University Press. 16 August 2011. p. 43. ISBN 978-0-19-538015-6. https://books.google.com/books?id=I1laHM-HP1QC&pg=PA43. Retrieved 17 May 2012. 
  9. ↑ "The effects of racemic D,L-methadone and L-methadone in substituted patients--a randomized controlled study". Drug and Alcohol Dependence 80 (2): 267–271. November 2005. doi:10.1016/j.drugalcdep.2005.04.007. PMID 15916866. 
  10. ↑ The Treatment of Opioid Dependence. JHU Press. 4 November 2005. p. 63. ISBN 978-0-8018-8303-3. https://books.google.com/books?id=entNMgTdeJ4C&pg=PA63. Retrieved 19 May 2012. 
  11. ↑ "Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs". The Journal of Pharmacology and Experimental Therapeutics 299 (1): 366–371. October 2001. doi:10.1016/S0022-3565(24)29338-1. PMID 11561100. 
  12. ↑ "The significance of chirality in drug design and development". Current Topics in Medicinal Chemistry 11 (7): 760–770. 2011. doi:10.2174/156802611795165098. PMID 21291399. 
  13. ↑ "Synthesis of Methadone". Erowid. https://www.erowid.org/archive/rhodium/chemistry/methadone.html. 
  14. ↑ "Synthesis of optically active methadones, LAAM and bufuralol by lipase-catalysed acylations". Tetrahedron: Asymmetry 14 (5): 567–576. March 2003. doi:10.1016/S0957-4166(03)00019-3. 
  15. ↑ Scheinmann F, Hull JD, Turner NJ, "Process for the preparation of optically active methadones in high enantiomeric purity", US patent 6143933, issued 7 November 2000, assigned to Salford Ultrafine Chemicals.
  16. ↑ "Levomethadone". Drugs.com. https://www.drugs.com/international/levomethadone.html. 
  17. ↑ "Conversion Factors for Controlled Substances". Diversion Control Division. Drug Enforcement Administration, United States Department of Justice. http://www.deadiversion.usdoj.gov/quotas/conv_factor/index.html. 
  18. ↑ "Opioid prescription patterns in Germany and the global opioid epidemic: Systematic review of available evidence". PLOS ONE 14 (8). 2019-08-28. doi:10.1371/journal.pone.0221153. PMID 31461466. Bibcode: 2019PLoSO..1421153R. 
  19. ↑ Reviewing Current Practice in Drug-substitution Treatment in the European Union. European Monitoring Centre for Drugs and Drug Addiction. 2000. ISBN 978-92-9168-104-4. https://www.emcdda.europa.eu/system/files/publications/111/Insight3_64348.pdf. [page needed]



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