From Wikipedia, the free encyclopedia
Synthetic opioid
Levomethadone
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
Legal status
Bioavailability High
[1]
Protein binding 60–90%
[1]
Elimination half-life ~18 hours
[1]
(6R )-6-(dimethylamino)-4,4-diphenyl-3-heptanone
CAS Number
PubChem
CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard
100.120.592
Formula C 21 H 27 N O
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]
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 exclusively 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
α3 β4 nicotinic acetylcholine (nACh) receptor .
[10]
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]
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.
[18] It is similarly controlled under the German
Betäubungsmittelgesetz and similar laws in practically every other country.
[19]
[20]
References
^
a
b
c
d
e
f 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 .
^
a
b
c
d Macdonald F (1997).
Dictionary of Pharmacological Agents . CRC Press. p. 1294.
ISBN
978-0-412-46630-4 . Retrieved 17 May 2012 .
^
a
b
c
Index Nominum 2000: International Drug Directory . Taylor & Francis US. 2000. p. 605.
ISBN
978-3-88763-075-1 . Retrieved 17 May 2012 .
^
a
b 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 .
S2CID
6051512 .
^
"Levomethadone - an overview | ScienceDirect Topics" . www.sciencedirect.com . Retrieved 2021-12-21 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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.
PMID
11561100 . Archived from
the original on 2021-08-28. Retrieved 2012-05-19 .
^ 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 .
^ 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 .
^ 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 .
^
"Synthesis of Methadone" . Erowid .
^ 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 .
^
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.
^
"Levomethadone" . Drugs.com . Archived from
the original on 3 March 2016.
^
"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 .
^ 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 .
^
"Reviewing current practice in drug-substitution treatment in the European Union" (PDF) .
Receptor (
ligands )
GlyR Tooltip Glycine receptor
Positive modulators:
Alcohols (e.g.,
brometone ,
chlorobutanol (chloretone) ,
ethanol (alcohol) ,
tert -butanol (2M2P) ,
tribromoethanol ,
trichloroethanol ,
trifluoroethanol )
Alkylbenzene sulfonate
Anandamide
Barbiturates (e.g.,
pentobarbital ,
sodium thiopental )
Chlormethiazole
D12-116
Dihydropyridines (e.g.,
nicardipine )
Etomidate
Ginseng constituents (e.g.,
ginsenosides (e.g.,
ginsenoside-Rf ))
Glutamic acid (glutamate)
Ivermectin
Ketamine
Neuroactive steroids (e.g.,
alfaxolone ,
pregnenolone (eltanolone) ,
pregnenolone acetate ,
minaxolone ,
ORG-20599 )
Nitrous oxide
Penicillin G
Propofol
Tamoxifen
Tetrahydrocannabinol
Triclofos
Tropeines (e.g.,
atropine ,
bemesetron ,
cocaine ,
LY-278584 ,
tropisetron ,
zatosetron )
Volatiles /
gases (e.g.,
chloral hydrate ,
chloroform ,
desflurane ,
diethyl ether (ether) ,
enflurane ,
halothane ,
isoflurane ,
methoxyflurane ,
sevoflurane ,
toluene ,
trichloroethane (methyl chloroform) ,
trichloroethylene )
Xenon
Zinc
Antagonists:
2-Aminostrychnine
2-Nitrostrychnine
4-Phenyl-4-formyl-N-methylpiperidine
αEMBTL
Bicuculline
Brucine
Cacotheline
Caffeine
Colchicine
Colubrine
Cyanotriphenylborate
Dendrobine
Diaboline
Endocannabinoids (e.g.,
2-AG ,
anandamide (AEA) )
Gaboxadol (THIP)
Gelsemine
iso-THAZ
Isobutyric acid
Isonipecotic acid
Isostrychnine
Laudanosine
N-Methylbicuculline
N-Methylstrychnine
N,N-Dimethylmuscimol
Nipecotic acid
Pitrazepin
Pseudostrychnine
Quinolines (e.g.,
4-hydroxyquinoline ,
4-hydroxyquinoline-3-carboxylic acid ,
5,7-CIQA ,
7-CIQ ,
7-TFQ ,
7-TFQA )
RU-5135
Sinomenine
Strychnine
Thiocolchicoside
Tutin
Negative modulators:
Amiloride
Benzodiazepines (e.g.,
bromazepam ,
clonazepam ,
diazepam ,
flunitrazepam ,
flurazepam )
Corymine
Cyanotriphenylborate
Daidzein
Dihydropyridines (e.g.,
nicardipine ,
nifedipine ,
nitrendipine )
Furosemide
Genistein
Ginkgo constituents (e.g.,
bilobalide ,
ginkgolides (e.g.,
ginkgolide A ,
ginkgolide B ,
ginkgolide C ,
ginkgolide J ,
ginkgolide M ))
Imipramine
NBQX
Neuroactive steroids (e.g.,
3α-androsterone sulfate ,
3β-androsterone sulfate ,
deoxycorticosterone ,
DHEA sulfate ,
pregnenolone sulfate ,
progesterone )
Opioids (e.g.,
codeine ,
dextromethorphan ,
dextrorphan ,
levomethadone ,
levorphanol ,
morphine ,
oripavine ,
pethidine ,
thebaine )
Picrotoxin (i.e.,
picrotin and
picrotoxinin )
PMBA
Riluzole
Tropeines (e.g.,
bemesetron ,
LY-278584 ,
tropisetron ,
zatosetron )
Verapamil
Zinc
NMDAR Tooltip N-Methyl-D-aspartate receptor
Transporter (
blockers )
GlyT1 Tooltip Glycine transporter 1
GlyT2 Tooltip Glycine transporter 2
AMPAR Tooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
KAR Tooltip Kainate receptor
NMDAR Tooltip N-Methyl-D-aspartate receptor
nAChRs Tooltip Nicotinic acetylcholine receptors
Agonists (and
PAMs Tooltip positive allosteric modulators )
5-HIAA
6-Chloronicotine
A-84,543
A-366,833
A-582,941
A-867,744
ABT-202
ABT-418
ABT-560
ABT-894
Acetylcholine
Altinicline
Anabasine
Anatabine
Anatoxin-a
AR-R17779
Bephenium hydroxynaphthoate
Butinoline
Butyrylcholine
Carbachol
Choline
Cotinine
Cytisine
Decamethonium
Desformylflustrabromine
Dianicline
Dimethylphenylpiperazinium
Epibatidine
Epiboxidine
Ethanol (alcohol)
Ethoxysebacylcholine
EVP-4473
EVP-6124
Galantamine
GTS-21
Ispronicline
Ivermectin
JNJ-39393406
Levamisole
Lobeline
MEM-63,908 (RG-3487)
Morantel
Nicotine (
tobacco )
NS-1738
PHA-543,613
PHA-709,829
PNU-120,596
PNU-282,987
Pozanicline
Pyrantel
Rivanicline
RJR-2429
Sazetidine A
SB-206553
Sebacylcholine
SIB-1508Y
SIB-1553A
SSR-180,711
Suberyldicholine
Suxamethonium (succinylcholine)
Suxethonium (succinyldicholine)
TC-1698
TC-1734
TC-1827
TC-2216
TC-5214
TC-5619
TC-6683
Tebanicline
Tribendimidine
Tropisetron
UB-165
Varenicline
WAY-317,538
XY-4083
Antagonists (and
NAMs Tooltip negative allosteric modulators )
Precursors (and
prodrugs )