Levomethadone

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]

Levomethadone

Clinical data
Other names	Levamethadone; 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	N07BC05 (WHO)
Legal status
Legal status	DE: Anlage III (Special prescription form required) UK: Class A US: Schedule II UN: Narcotic Schedule I
Pharmacokinetic data
Bioavailability	High[1]
Protein binding	60–90%[1]
Elimination half-life	~18 hours[1]
Identifiers
IUPAC name (6R)-6-(dimethylamino)-4,4-diphenyl-3-heptanone
CAS Number	125-58-6 5967-73-7 (HCl)
PubChem CID	22267
ChemSpider	20904
UNII	6Y75Z4E8NS
KEGG	D08121
ChEBI	CHEBI:136003
ChEMBL	ChEMBL159659
ECHA InfoCard	100.120.592
Chemical and physical data
Formula	C21H27NO
Molar mass	309.445 g·mol^−1
3D model (JSmol)	Interactive image
Melting point	99.5 °C (211.1 °F)
Solubility in water	48.48 mg/mL (20 °C)
SMILES O=C(C(c1ccccc1)(c2ccccc2)C[C@H](N(C)C)C)CC
InChI 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

Where it is used, levomethadone is used for narcotic maintenance in place of, or in some cases alongside as an alternative, to racemic methadone, owing to concern about the cardiotoxic and QT-prolonging action of racemic methadone being exclusively caused by the dextrorotatory enantiomer, dextromethadone.

Pharmacology

Pharmacodynamics

Levomethadone has approximately 50x the potency of the S-(+)-enantiomer as well as greater μ-opioid receptor selectivity.[1][4] Accordingly, it is about twice as potent as methadone by weight and its effects are virtually identical in comparison.[5][6] 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[7] and as a potent noncompetitive antagonist of the α₃β₄ nicotinic acetylcholine (nACh) receptor.[8]

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. 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 levo-methadone can easily be retrieved from the mother liquor in a high state of optical purity" [9]

There is now an asymmetric synthesis[10] available to prepare both levomethadone (R-(−)-methadone) and dextromethadone (S-(+)-methadone).[11]

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, and Vistadict, among others.[12][3][2]

Legal status

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.[13] It is similarly controlled under the German Betäubungsmittelgesetz and similar laws in practically every other country.

References

1. Helmut Buschmann (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. F.. Macdonald (1997). Dictionary of Pharmacological Agents. CRC Press. p. 1294. ISBN 978-0-412-46630-4. Retrieved 17 May 2012.
3. Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 605. ISBN 978-3-88763-075-1. Retrieved 17 May 2012.
4. Renate Förch; Holger Schönherr; A. Tobias A. Jenkins (11 August 2009). Surface Design: Applications in Bioscience and Nanotechnology. Wiley-VCH. p. 193. ISBN 978-3-527-40789-7. Retrieved 17 May 2012.
5. Eduardo Bruera; Sriram Yennurajalingam (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.
6. Verthein U, Ullmann R, Lachmann A, 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): 267–71. doi:10.1016/j.drugalcdep.2005.04.007. PMID 15916866.
7. Eric C. Strain; Maxine L. Stitzer (4 November 2005). The Treatment of Opioid Dependence. JHU Press. p. 63. ISBN 978-0-8018-8303-3. Retrieved 19 May 2012.
8. 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): 366–71. PMID 11561100.
9. https://www.erowid.org/archive/rhodium/chemistry/methadone.html
10. 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.
11. US patent 6143933
12. https://www.drugs.com/international/levomethadone.html
13. http://www.deadiversion.usdoj.gov/quotas/conv_factor/index.html