Levacetylmethadol

Identification

Name
Levacetylmethadol
Accession Number
DB01227
Description

A narcotic analgesic with a long onset and duration of action. It is used mainly in the treatment of narcotic dependence.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 353.4977
Monoisotopic: 353.235479241
Chemical Formula
C23H31NO2
Synonyms
  • (-)-alpha-Acetylmethadol
  • (1S,4S)-4-(dimethylamino)-1-ethyl-2,2-diphenylpentyl acetate
  • 1-alpha-Acetylmethadol
  • LAAM
  • Levacetilmetadol
  • Levacetylmethadol
  • Levacetylmethadolum
  • Levo-alpha-acetylmethadol
  • Levo-methadyl acetate
  • Levo-α-acetylmethadol
  • Levomethadyl
  • Levomethadyl acetate

Pharmacology

Indication

For the treatment and management of opiate dependence. It is sometimes used to treat severe pain in terminal patients.

Contraindications & Blackbox Warnings
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Pharmacodynamics

Levomethadyl acetate (also known as LAAM) is a synthetic synthetic opioid analgesic with multiple actions quantitatively similar to those as morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. However, levomethadyl acetate is more active and more toxic than morphine. The principal actions of therapeutic value are analgesia and sedation and detoxification or temporary maintenance in narcotic addiction. In this respect, the drug is similar to Methadone and also has structural similarities to it. The levomethadyl acetate abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe.

Mechanism of action

Opiate receptors (Mu, Kappa, Delta) are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Levomethadyl acetate effectively opens calcium-dependent inwardly rectifying potassium channels (OP1 receptor agonist), resulting in hyperpolarization and reduced neuronal excitability.

TargetActionsOrganism
AMu-type opioid receptor
agonist
Humans
UNeuronal acetylcholine receptor subunit beta-4
other/unknown
Humans
UNeuronal acetylcholine receptor subunit alpha-3
antagonist
Humans
Absorption

Levomethadyl acetate is rapidly absorbed from an oral solution.

Volume of distribution
Not Available
Protein binding

Approximately 80%

Metabolism

Levomethadyl acetate is demethylated to nor-levomethadyl acetate which is again demethylated to dinor-levomethadyl acetate. This extensive first pass metabolism produces 2 metabolites that are more active than the parent drug.

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Route of elimination
Not Available
Half-life

2.6 days

Clearance
Not Available
Adverse Effects
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Toxicity

Signs of overdose include apnea, circulatory collapse, pulmonary edema, cardiac arrest, and death.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Levomethadyl Acetate Action Action PathwayDrug action
Levomethadyl Acetate Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Levacetylmethadol can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Levacetylmethadol can be increased when combined with Abatacept.
AcalabrutinibThe metabolism of Levacetylmethadol can be decreased when combined with Acalabrutinib.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Levacetylmethadol.
AcetaminophenThe metabolism of Levacetylmethadol can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Levacetylmethadol can be decreased when combined with Acetazolamide.
AcetophenazineThe risk or severity of hypotension and CNS depression can be increased when Acetophenazine is combined with Levacetylmethadol.
AclidiniumThe risk or severity of adverse effects can be increased when Levacetylmethadol is combined with Aclidinium.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Levacetylmethadol.
AdalimumabThe metabolism of Levacetylmethadol can be increased when combined with Adalimumab.
Additional Data Available
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    Extended Description
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    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity
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    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level
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  • Action
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Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Levacetylmethadol hydrochlorideB54CW5KG5243033-72-3UXBPQRGCVJOTNT-COBSGTNCSA-N
International/Other Brands
Orlaam

Categories

ATC Codes
N07BC03 — Levacetylmethadol
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Aralkylamines / Trialkylamines / Carboxylic acid esters / Amino acids and derivatives / Monocarboxylic acids and derivatives / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Amine / Amino acid or derivatives / Aralkylamine / Aromatic homomonocyclic compound / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Diphenylmethane / Hydrocarbon derivative / Monocarboxylic acid or derivatives
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
tertiary amino compound, acetate ester (CHEBI:6441)

Chemical Identifiers

UNII
R3B637Y991
CAS number
1477-40-3
InChI Key
XBMIVRRWGCYBTQ-AVRDEDQJSA-N
InChI
InChI=1S/C23H31NO2/c1-6-22(26-19(3)25)23(17-18(2)24(4)5,20-13-9-7-10-14-20)21-15-11-8-12-16-21/h7-16,18,22H,6,17H2,1-5H3/t18-,22-/m0/s1
IUPAC Name
(3S,6S)-6-(dimethylamino)-4,4-diphenylheptan-3-yl acetate
SMILES
CC[[email protected]](OC(C)=O)C(C[[email protected]](C)N(C)C)(C1=CC=CC=C1)C1=CC=CC=C1

References

General References
Not Available
Human Metabolome Database
HMDB0015358
KEGG Drug
D04716
KEGG Compound
C08012
PubChem Compound
15130
PubChem Substance
46507749
ChemSpider
14401
RxNav
237005
ChEBI
6441
ChEMBL
CHEMBL1514
ZINC
ZINC000001530967
Therapeutic Targets Database
DAP001139
PharmGKB
PA450215
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Levacetylmethadol

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentHeroin Dependence / Opioid-Related Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility>15 mg/mLNot Available
logP5.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00179 mg/mLALOGPS
logP4.78ALOGPS
logP4.88ChemAxon
logS-5.3ALOGPS
pKa (Strongest Basic)9.87ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area29.54 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity117.86 m3·mol-1ChemAxon
Polarizability40.53 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9965
Blood Brain Barrier+0.9648
Caco-2 permeable+0.7459
P-glycoprotein substrateSubstrate0.5822
P-glycoprotein inhibitor IInhibitor0.8472
P-glycoprotein inhibitor IINon-inhibitor0.8897
Renal organic cation transporterNon-inhibitor0.6473
CYP450 2C9 substrateNon-substrate0.7976
CYP450 2D6 substrateNon-substrate0.8641
CYP450 3A4 substrateSubstrate0.6658
CYP450 1A2 substrateInhibitor0.5619
CYP450 2C9 inhibitorNon-inhibitor0.8153
CYP450 2D6 inhibitorInhibitor0.7123
CYP450 2C19 inhibitorNon-inhibitor0.7312
CYP450 3A4 inhibitorInhibitor0.5242
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5811
Ames testNon AMES toxic0.9016
CarcinogenicityCarcinogens 0.7025
BiodegradationNot ready biodegradable0.9792
Rat acute toxicity3.3406 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9706
hERG inhibition (predictor II)Inhibitor0.7157
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
References
  1. Yu Y, Zhang L, Yin X, Sun H, Uhl GR, Wang JB: Mu opioid receptor phosphorylation, desensitization, and ligand efficacy. J Biol Chem. 1997 Nov 14;272(46):28869-74. [PubMed:9360954]
  2. Skoulis NP, James RC, Harbison RD, Roberts SM: Depression of hepatic glutathione by opioid analgesic drugs in mice. Toxicol Appl Pharmacol. 1989 Jun 1;99(1):139-47. [PubMed:2471291]
  3. Kreek MJ: Methadone-related opioid agonist pharmacotherapy for heroin addiction. History, recent molecular and neurochemical research and future in mainstream medicine. Ann N Y Acad Sci. 2000;909:186-216. [PubMed:10911931]
  4. Xiao Y, Smith RD, Caruso FS, Kellar KJ: Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs. J Pharmacol Exp Ther. 2001 Oct;299(1):366-71. [PubMed:11561100]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Other/unknown
General Function
Ligand-gated ion channel activity
Specific Function
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Gene Name
CHRNB4
Uniprot ID
P30926
Uniprot Name
Neuronal acetylcholine receptor subunit beta-4
Molecular Weight
56378.985 Da
References
  1. Xiao Y, Smith RD, Caruso FS, Kellar KJ: Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs. J Pharmacol Exp Ther. 2001 Oct;299(1):366-71. [PubMed:11561100]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Ligand-gated ion channel activity
Specific Function
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Gene Name
CHRNA3
Uniprot ID
P32297
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-3
Molecular Weight
57479.54 Da
References
  1. Xiao Y, Smith RD, Caruso FS, Kellar KJ: Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs. J Pharmacol Exp Ther. 2001 Oct;299(1):366-71. [PubMed:11561100]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Oda Y, Kharasch ED: Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation. J Pharmacol Exp Ther. 2001 Sep;298(3):1021-32. [PubMed:11504799]
  2. Kharasch ED, Whittington D, Hoffer C, Krudys K, Craig K, Vicini P, Sheffels P, Lalovic B: Paradoxical role of cytochrome P450 3A in the bioactivation and clinical effects of levo-alpha-acetylmethadol: importance of clinical investigations to validate in vitro drug metabolism studies. Clin Pharmacokinet. 2005;44(7):731-51. doi: 10.2165/00003088-200544070-00005. [PubMed:15966756]
  3. Flockhart Table of Drug Interactions [Link]

Drug created on June 13, 2005 07:24 / Updated on November 09, 2020 17:11

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