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Identification
NameLevomethadyl Acetate
Accession NumberDB01227  (APRD00745)
TypeSmall Molecule
GroupsApproved
Description

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

Structure
Thumb
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
Orlaam
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
OrlaamNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Levomethadyl acetate hydrochloride
ThumbNot applicableDBSALT001444
Categories
UNIIR3B637Y991
CAS number1477-40-3
WeightAverage: 353.4977
Monoisotopic: 353.235479241
Chemical FormulaC23H31NO2
InChI KeyInChIKey=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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassDiphenylmethanes
Direct ParentDiphenylmethanes
Alternative Parents
Substituents
  • Diphenylmethane
  • Phenylpropylamine
  • Aralkylamine
  • Acetate salt
  • Tertiary aliphatic amine
  • Tertiary amine
  • Carboxylic acid ester
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment and management of opiate dependence. It is sometimes used to treat severe pain in terminal patients.
PharmacodynamicsLevomethadyl 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 actionOpiate 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.
Related Articles
AbsorptionLevomethadyl acetate is rapidly absorbed from an oral solution.
Volume of distributionNot Available
Protein bindingApproximately 80%
Metabolism

Levomethadyl acetate undergoes extensive first-pass metabolism to the active demethylated metabolite nor-levomethadyl acetate, which is further demethylated to a second active metabolite, dinor-levomethadyl acetate. These metabolites are more potent than the parent drug.

SubstrateEnzymesProduct
Levomethadyl Acetate
noracymethadolDetails
Levomethadyl Acetate
Nor-levomethadyl acetate (nor-LAAM)Details
Nor-levomethadyl acetate (nor-LAAM)
Dinor-levomethadyl acetateDetails
Route of eliminationNot Available
Half life2.6 days
ClearanceNot Available
ToxicitySigns of overdose include apnea, circulatory collapse, pulmonary edema, cardiac arrest, and death.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Levomethadyl Acetate Action Action PathwayDrug actionSMP00677
Levomethadyl Acetate Metabolism PathwayDrug metabolismSMP00638
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
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 RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesN07BC03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
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. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociati...
Gene Name:
OPRM1
Uniprot ID:
P35372
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
Human
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
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
Human
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
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
Human
Pharmacological action
unknown
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  2. 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 ]
  3. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Molecular Weight:
57108.065 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A7
Uniprot ID:
P24462
Molecular Weight:
57525.03 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxygen binding
Specific Function:
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name:
CYP19A1
Uniprot ID:
P11511
Molecular Weight:
57882.48 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on June 13, 2005 07:24 / Updated on November 30, 2015 12:10