Levomethadone

Last updated

Levomethadone
Levomethadone structure.svg
Levomethadone-xtal-1974-ball-and-stick.png
Clinical data
Other namesLevamethadone; l-Methadone; 6R-Methadone; (–)-Methadone; R-(–)-Methadone; D-(–)-Methadone
AHFS/Drugs.com International Drug Names
Routes of
administration 		By mouth, IV, IM, SC, IT [1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability High [1]
Protein binding 60–90% [1]
Elimination half-life ~18 hours [1]
Identifiers
  • (6R)-6-(dimethylamino)-4,4-diphenyl-3-heptanone
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.120.592 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H27NO
Molar mass 309.453 g·mol−1
3D model (JSmol)
Melting point 99.5 °C (211.1 °F)
Solubility in water 48.48 mg/mL (20 °C)
  • O=C(C(c1ccccc1)(c2ccccc2)C[C@H](N(C)C)C)CC
  • InChI=1S/C21H27NO/c1-5-20(23)21(16-17(2)22(3)4,18-12-8-6-9-13-18)19-14-10-7-11-15-19/h6-15,17H,5,16H2,1-4H3/t17-/m1/s1
  • Key:USSIQXCVUWKGNF-QGZVFWFLSA-N

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 the main therapeutic component of methadone. [2]

Contents

Levomethadone is used for narcotic maintenance in place of, or in some cases alongside as an alternative, to racemic methadone, [4] owing to concern about the cardiotoxic and QT-prolonging action of racemic methadone being primarily caused by the dextrorotatory enantiomer, dextromethadone. [5] [4]

Pharmacology

Pharmacodynamics

Levomethadone has approximately 50x the potency of the S-(+)-enantiomer as well as greater μ-opioid receptor selectivity. [1] [6] Accordingly, it is about twice as potent as methadone by weight and its effects are virtually identical in comparison. [7] [8] 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 [9] and as a potent noncompetitive antagonist of the α3β4 nicotinic acetylcholine (nACh) receptor. [10]

Receptor binding affinities of isomers of methadone [11] [12]
Compound Affinities (Ki Tooltip Inhibitor constant, in nM)Ratios
MOR Tooltip μ-Opioid receptor DOR Tooltip δ-Opioid receptor KOR Tooltip κ-Opioid receptor SERT Tooltip Serotonin transporter NET Tooltip Norepinephrine transporter NMDAR Tooltip N-Methyl-D-aspartate receptorM:D:KSERT:NET
Racemic methadone 1.74354051,4002592,500–8,3001:256:2381:5
Dextromethadone 19.79601,37099212,7002,600–7,4001:49:701:13
Levomethadone0.9453711,86014.17022,800–3,4001:393:19681:50

Chemistry

The separation of the stereoisomers is one of the easier in organic chemistry and is described in the original patent. [13] 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." [14]

There is now an asymmetric synthesis [15] available to prepare both levomethadone (R-(−)-methadone) and dextromethadone (S-(+)-methadone). [16]

Society and culture

Generic names

Levomethadone is the generic name of the drug and its INN Tooltip International Nonproprietary Name. [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. [17] [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. [18] It is similarly controlled under the German Betäubungsmittelgesetz and similar laws in practically every other country. [19] [20]

References

  1. 1 2 3 4 5 6 Buschmann H (20 December 2002). Analgesics: From Chemistry and Pharmacology to Clinical Application. Wiley-VCH. p. 196. ISBN   978-3-527-30403-5 . Retrieved 17 May 2012.
  2. 1 2 3 4 Macdonald F (1997). Dictionary of Pharmacological Agents. CRC Press. p. 1294. ISBN   978-0-412-46630-4 . Retrieved 17 May 2012.
  3. 1 2 3 Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 605. ISBN   978-3-88763-075-1 . Retrieved 17 May 2012.
  4. 1 2 Judson BA, Horns WH, Goldstein A (October 1976). "Side effects of levomethadone and racemic methadone in a maintenance program". Clinical Pharmacology and Therapeutics. 20 (4): 445–449. doi:10.1002/cpt1976204445. PMID   788990.
  5. ↑ Eap CB, Crettol S, Rougier JS, Schläpfer J, Sintra Grilo L, Déglon JJ, et al. (May 2007). "Stereoselective Block of hERG Channel by (S)-Methadone and QT Interval Prolongation in CYP2B6 Slow Metabolizers". Clinical Pharmacology and Therapeutics. 81 (5): 719–728. doi:10.1038/sj.clpt.6100120. PMID   17329992.
  6. ↑ Förch R, Schönherr H, Tobias A, Jenkins A (11 August 2009). Surface Design: Applications in Bioscience and Nanotechnology. Wiley-VCH. p. 193. ISBN   978-3-527-40789-7 . Retrieved 17 May 2012.
  7. ↑ Bruera E, Yennurajalingam S (16 August 2011). Oxford American Handbook of Hospice and Palliative Medicine. Oxford University Press. p. 43. ISBN   978-0-19-538015-6 . Retrieved 17 May 2012.
  8. ↑ Verthein U, Ullmann R, Lachmann A, Düring A, Koch B, Meyer-Thompson HG, et al. (November 2005). "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. doi:10.1016/j.drugalcdep.2005.04.007. PMID   15916866.
  9. ↑ Strain EC, Stitzer ML (4 November 2005). The Treatment of Opioid Dependence. JHU Press. p. 63. ISBN   978-0-8018-8303-3 . Retrieved 19 May 2012.
  10. ↑ Xiao Y, Smith RD, Caruso FS, Kellar KJ (October 2001). "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. doi:10.1016/S0022-3565(24)29338-1. PMID   11561100.
  11. ↑ Codd EE, Shank RP, Schupsky JJ, Raffa RB (1995). "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". J. Pharmacol. Exp. Ther. 274 (3): 1263–70. PMID   7562497.
  12. ↑ Gorman AL, Elliott KJ, Inturrisi CE (February 1997). "The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord". Neurosci. Lett. 223 (1): 5–8. doi:10.1016/S0304-3940(97)13391-2. PMID   9058409.
  13. ↑ Brooks WH, Guida WC, Daniel KG (2011). "The significance of chirality in drug design and development". Current Topics in Medicinal Chemistry. 11 (7): 760–770. doi:10.2174/156802611795165098. PMC   5765859 . PMID   21291399.
  14. ↑ "Synthesis of Methadone". Erowid.
  15. ↑ Hull JD, Scheinmann F, Turner NJ (March 2003). "Synthesis of optically active methadones, LAAM and bufuralol by lipase-catalysed acylations". Tetrahedron: Asymmetry. 14 (5): 567–576. doi:10.1016/S0957-4166(03)00019-3.
  16. ↑ US 6143933,Scheinmann F, Hull JD, Turner NJ,"Process for the preparation of optically active methadones in high enantiomeric purity",issued 7 November 2000, assigned to Salford Ultrafine Chemicals.
  17. ↑ "Levomethadone". Drugs.com. Archived from the original on 3 March 2016.
  18. ↑ "Conversion Factors for Controlled Substances". Diversion Control Division. Drug Enforcement Administration, United States Department of Justice. Archived from the original on 2016-03-02. Retrieved 2014-08-21.
  19. ↑ Rosner B, Neicun J, Yang JC, Roman-Urrestarazu A (2019-08-28). Cheungpasitporn W (ed.). "Opioid prescription patterns in Germany and the global opioid epidemic: Systematic review of available evidence". PLOS ONE. 14 (8): e0221153. Bibcode:2019PLoSO..1421153R. doi: 10.1371/journal.pone.0221153 . PMC   6713321 . PMID   31461466.
  20. ↑ Robertson K, Solberg U (2000). Reviewing Current Practice in Drug-substitution Treatment in the European Union (PDF). European Monitoring Centre for Drugs and Drug Addiction. ISBN   978-92-9168-104-4.[ page needed ]
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