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
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]

Related Research Articles

<span class="mw-page-title-main">Methadone</span> Opioid medication

Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid use disorder. It is used to treat chronic pain, and it is also used to treat addiction to heroin or other opioids. Prescribed for daily use, the medicine relieves cravings and removes withdrawal symptoms. Withdrawal management using methadone can be accomplished in less than a month, or it may be done gradually over a longer period of time, or simply maintained for the rest of the patient's life. While a single dose has a rapid effect, maximum effect can take up to five days of use. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.

<span class="mw-page-title-main">Narcotic</span> Chemical substance with psycho-active properties

The term narcotic originally referred medically to any psychoactive compound with numbing or paralyzing properties. In the United States, it has since become associated with opiates and opioids, commonly morphine and heroin, as well as derivatives of many of the compounds found within raw opium latex. The primary three are morphine, codeine, and thebaine.

In chemistry, a racemic mixture or racemate, is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates.

<span class="mw-page-title-main">Tramadol</span> Medication of the opioid type, patented 1972

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic form. This creates a 1:1 molar ratio of enantiomers and is referred to as a racemic mixture. Plus and minus forms are called Dextrorotation and levorotation. The D and L enantiomers are present in equal quantities, the resulting sample is described as a racemic mixture or a racemate. Racemization can proceed through a number of different mechanisms, and it has particular significance in pharmacology as different enantiomers may have different pharmaceutical effects.

<span class="mw-page-title-main">Epibatidine</span> Toxic chemical from some poison dart frogs

Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi and poison dart frogs from the Ameerega genus. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine.

<span class="mw-page-title-main">Levorphanol</span> Opioid analgesic drug

Levorphanol is an opioid medication used to treat moderate to severe pain. It is the levorotatory enantiomer of the compound racemorphan. Its dextrorotatory counterpart is dextrorphan.

<span class="mw-page-title-main">Methorphan</span> Group of stereoisomers

Methorphan comes in two isomeric forms, each with differing pharmacology and effects:

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for human and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">Levacetylmethadol</span> Synthetic opioid drug

Levacetylmethadol (INN), levomethadyl acetate (USAN), OrLAAM or levo-α-acetylmethadol (LAAM) is a synthetic opioid similar in structure to methadone. It has a long duration of action due to its active metabolites.

<span class="mw-page-title-main">Alphamethadol</span> Synthetic opioid analgesic drug

Alphamethadol (INN), or α-methadol, also known as alfametadol, is a synthetic opioid analgesic. It is an isomer of dimepheptanol (methadol), the other being betamethadol (β-methadol). Alphamethadol is composed of two isomers itself, L-α-methadol, and D-α-methadol. The former compound, L-α-methadol, is an important active metabolite of levacetylmethadol (LAAM), an opioid substitute drug that is used clinically. Both of alphamethadol's isomers bind to and activate the μ-opioid receptor and are active as opioid analgesics, similarly to those of alphacetylmethadol (α-acetylmethadol).

An equianalgesic chart is a conversion chart that lists equivalent doses of analgesics. Equianalgesic charts are used for calculation of an equivalent dose between different analgesics. Tables of this general type are also available for NSAIDs, benzodiazepines, depressants, stimulants, anticholinergics and others.

<span class="mw-page-title-main">Alazocine</span> Synthetic opioid analgesic

Alazocine, also known more commonly as N-allylnormetazocine (NANM), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. In addition to its opioid activity, the drug is a sigma receptor agonist, and has been used widely in scientific research in studies of this receptor. Alazocine is described as a potent analgesic, psychotomimetic or hallucinogen, and opioid antagonist. Moreover, one of its enantiomers was the first compound that was found to selectively label the σ1 receptor, and led to the discovery and characterization of the receptor.

<span class="mw-page-title-main">Arylcyclohexylamine</span> Class of chemical compounds

Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of pharmaceutical, designer, and experimental drugs.

The eudysmic ratio represents the difference in pharmacologic activity between the two enantiomers of a drug. In most cases where a chiral compound is biologically active, one enantiomer is more active than the other. The eudysmic ratio is the ratio of activity between the two. A eudysmic ratio significantly differing from 1 means that they are statistically different in activity. Eudisimic ratio (ER) reflects the degree of enantioselectivity of the biological systems. For example, (S)-propranolol meaning that (S)-propranolol is 130 times more active than its (R)-enantiomer.

<span class="mw-page-title-main">Isomethadone</span> Opioid analgesic and cough suppressant drug

Isomethadone (INN, BAN; trade name Liden; also known as isoamidone) is a synthetic opioid analgesic and antitussive related to methadone that was used formerly as a pharmaceutical drug but is now no longer marketed. Isomethadone was used as both an analgesic and antitussive. It binds to and activates both the μ- and δ-opioid receptors, with the (S)-isomer being the more potent of the two enantiomers. Isomethadone is a Schedule II controlled substance in the United States, with an ACSCN of 9226 and a 2014 aggregate manufacturing quota of 5 g. The salts in use are the hydrobromide (HBr, free base conversion ratio 0.793), hydrochloride (HCl, 0.894), and HCl monohydrate (0.850). Isomethadone is also regulated internationally as a Schedule I controlled substance under the United Nations Single Convention on Narcotic Drugs of 1961.

<span class="mw-page-title-main">(+)-Naloxone</span> Drug

(+)-Naloxone (dextro-naloxone) is a drug which is the opposite enantiomer of the opioid antagonist drug (−)-naloxone. Unlike (−)-naloxone, (+)-naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4. This receptor is involved in immune system responses, and activation of TLR4 induces glial activation and release of inflammatory mediators such as TNF-α and Interleukin-1.

<span class="mw-page-title-main">MT-45</span> Chemical compound

MT-45 (IC-6) is an opioid analgesic drug invented in the 1970s by Dainippon Pharmaceutical Co. It is chemically a 1-substituted-4-(1,2-diphenylethyl) piperazine derivative, which is structurally unrelated to most other opioid drugs. Racemic MT-45 has around 80% the potency of morphine, with almost all opioid activity residing in the (S) enantiomer. It has been used as a lead compound from which a large family of potent opioid drugs have been developed, including full agonists, partial agonists, and antagonists at the three main opioid receptor subtypes. Fluorinated derivatives of MT-45 such as 2F-MT-45 are significantly more potent as μ-opioid receptor agonists, and one of its main metabolites 1,2-diphenylethylpiperazine also blocks NMDA receptors.

<span class="mw-page-title-main">Esmethadone</span> (S)-enantiomer of methadone

Esmethadone (INNTooltip International Nonproprietary Name; developmental code name REL-1017), also known as dextromethadone, is the (S)-enantiomer of methadone. It acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist, among other actions. Unlike levomethadone, it has low affinity for opioid receptors and lacks significant respiratory depressant action and abuse liability. Esmethadone is under development for the treatment of major depressive disorder. As of August 2022, it is in phase 3 clinical trials for this indication.

<span class="mw-page-title-main">Norketamine</span> Major active metabolite of ketamine

Norketamine, or N-desmethylketamine, is the major active metabolite of ketamine, which is formed mainly by CYP3A4. Similarly to ketamine, norketamine acts as a noncompetitive NMDA receptor antagonist, but is about 3–5 times less potent as an anesthetic in comparison.

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. S2CID   6051512.
  5. ↑ "Levomethadone - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2021-12-21.
  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. PMID   11561100. Archived from the original on 2021-08-28. Retrieved 2012-05-19.
  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. ↑ "Reviewing current practice in drug-substitution treatment in the European Union" (PDF).
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