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targets (3) enzymes (4)
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Identification
Name Levomethadyl Acetate
Accession Number DB01227 (APRD00745)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • 1-alpha-acetylmethadol
  • LAAM
  • Levacetilmetadol [INN-Spanish]
  • Levacetylmethadol
  • Levacetylmethadolum [INN-Latin]
  • Levo-Alphacetylmethadol
  • Levo-Methadyl Acetate
  • Levomethadyl
  • Nor-LAAM
Brand names
  • Orlaam
Brand name mixtures Not Available
Categories
  • Narcotics
  • Analgesics, Opioid
CAS number 1477-40-3
Weight Average: 353.4977
Monoisotopic: 353.235479241
Chemical Formula C23H31NO2
InChI Key InChIKey=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
Plain Text
IUPAC Name
(3S,6S)-6-(dimethylamino)-4,4-diphenylheptan-3-yl acetate
SMILES
CC[C@H](OC(C)=O)C(C[C@H](C)N(C)C)(C1=CC=CC=C1)C1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Diphenylmethanes
Substructures
  • Carboxylic Acids and Derivatives
  • Acetates
  • Ethers
  • Benzene and Derivatives
  • Cumenes and Derivatives
  • Aliphatic and Aryl Amines
  • Diphenylmethanes
  • Aromatic compounds
  • Phenylpropylamines
Pharmacology
Indication For the treatment and management of opiate dependence. It is sometimes used to treat severe pain in terminal patients.
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.
Absorption Levomethadyl acetate is rapidly absorbed from an oral solution.
Volume of distribution Not Available
Protein binding Approximately 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.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 3A4 noracymethadol N-demethylation 8 71.5
Route of elimination Not Available
Half life 2.6 days
Clearance Not Available
Toxicity Signs of overdose include apnea, circulatory collapse, pulmonary edema, cardiac arrest, and death.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Roxane laboratories inc
Packagers Not Available
Dosage forms
Form Route Strength
Solution, concentrate Oral
Prices Not Available
Patents Not Available
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility >15 mg/mL PhysProp
logP 5.4 PhysProp
Predicted Properties
Property Value Source
water solubility 1.79e-03 g/l ALOGPS
logP 4.78 ALOGPS
logP 4.88 ChemAxon Molconvert
logS -5.30 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 29.54 ChemAxon Molconvert
rotatable bond count 9 ChemAxon Molconvert
refractivity 117.86 ChemAxon Molconvert
polarizability 40.53 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D04716 Link_out
KEGG Compound C08012 Link_out
PubChem Compound 15130 Link_out
PubChem Substance 46507749 Link_out
ChemSpider 14401 Link_out
ChEBI 6441 Link_out
ChEMBL 6441 Link_out
Therapeutic Targets Database DAP001139 Link_out
PharmGKB PA450215 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic2/levomethadyl.htm Link_out
Drugs.com http://www.drugs.com/cons/levomethadyl.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Levomethadyl_Acetate Link_out
ATC Codes Not Available
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Mu-type opioid receptor

Pharmacological action: yes
Actions: agonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for beta-endorphin

Organism class: human
UniProt ID: P35372 Link_out
Gene: OPRM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
  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
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Neuronal acetylcholine receptor subunit beta-4

Pharmacological action: unknown
Actions: other/unknown

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

Organism class: human
UniProt ID: P30926 Link_out
Gene: CHRNB4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

3. Neuronal acetylcholine receptor subunit alpha-3

Pharmacological action: unknown
Actions: antagonist

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

Organism class: human
UniProt ID: P32297 Link_out
Gene: CHRNA3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes

1. Cytochrome P450 3A5

Actions: substrate

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

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

2. Cytochrome P450 3A7

Actions: substrate

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

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A4

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. 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. Epub 2009 Nov 24. Pubmed
  3. 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

4. Cytochrome P450 19A1

Actions: substrate

Catalyzes the formation of aromatic C18 estrogens from C19 androgens

UniProt ID: P11511 Link_out
Gene: CYP19A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 14, 2010 12:16

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.