Showing drug card for Levomethadyl Acetate (DB01227)

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Version

2.5

Creation Date

2005-06-13 13:24:05

Update Date

2009-06-23 18:05:50

Primary Accession Number

DB01227

Secondary Accession Number

APRD00745

Name

Levomethadyl Acetate

Drug Type

Approved
Small Molecule

Description

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

Synonyms

1-alpha-acetylmethadol
LAAM
Levacetilmetadol [INN-Spanish]
Levacetylmethadol
Levacetylmethadolum [INN-Latin]
Levo-Alphacetylmethadol
Levo-Methadyl Acetate
Levomethadyl
Nor-LAAM

Brand Names

Orlaam

Brand Mixtures

Not Available

Chemical IUPAC Name

[(3S,6S)-6-dimethylamino-4,4-di(phenyl)heptan-3-yl] acetate

Chemical Formula

C₂₃H₃₁NO₂

Chemical Structure

CAS Registry Number

1477-40-3

InChI Identifier

InChI=1/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

InChI Key

XBMIVRRWGCYBTQ-AVRDEDQJBI

KEGG Drug

KEGG Compound

PubChem Compound

PubChem Substance

ChEBI ID

PharmGKB ID

HET ID

Not Available

GenBank ID

Not Available

Drug ID Number [DIN]

Not Available

RxList Link

http://www.rxlist.com/cgi/generic2/levomethadyl.htm Link Image

PDRhealth Link

Not Available

Wikipedia Link

http://en.wikipedia.org/wiki/Levomethadyl_Acetate Link Image

FDA Label

Not Available

Material Safety Data Sheet (MSDS)

Not Available

Synthesis Reference

Not Available

Average Molecular Weight

353.4977

Monoisotopic Molecular Weight

353.2355

State

Solid

Melting Point

Not Available

Experimental Water Solubility

>15 mg/mL Source: PhysProp

Predicted Water Solubility

1.79e-03 mg/mL Calculated using ALOGPS

Experimental LogP/Hydrophobicity

5.4 Source: PhysProp

Predicted LogP

4.78 Calculated using ALOGPS

Experimental LogS

Not Available

Predicted LogS

-5.30 Calculated using ALOGPS

Experimental Caco2 Permeability

Not Available

pKa/Isoelectric Point

Not Available

Mass Spectrum

Not Available

MOL File

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SDF File

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PDB File

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2D Structure

3D Structure

Experimental PDB ID

Not Available

Isomeric SMILES

CC[C@H](OC(C)=O)C(C[C@H](C)N(C)C)(C1=CC=CC=C1)C1=CC=CC=C1

Canonical SMILES

CCC(OC(C)=O)C(CC(C)N(C)C)(C1=CC=CC=C1)C1=CC=CC=C1

Drug Category

Analgesics, Opioid
Narcotics

ATC Codes

Not Available

AHFS Codes

Not Available

Indication

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

Pharmacology

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. 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 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.

Toxicity

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

Protein Binding

Approximately 80%

Biotransformation

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.

Half Life

2.6 days

Dosage Forms

Form	Route
Solution, concentrate	Oral

Patient Information

Not Available

Contraindications

Show

Interactions

Not Available

Drug Interactions

Not Available

Food Interactions

Not Available

Pathways

Not Available

General References

Organisms Affected

Humans and other mammals

Phase 1 Metabolizing Enzymes

Cytochrome P450 3A4 (CYP3A4)

Targets

Mu-type opioid receptor

Phase 1 Metabolizing Enzyme 1 [top]
Enzyme 1 Name	Cytochrome P450 3A4 (CYP3A4)
Enzyme 1 Gene Name	CYP3A4
Enzyme 1 SwissProt ID	P08684
Enzyme 1 SNPs	SNPJam Report
Enzyme 1 Protein Sequence	>sp\|P08684\|CP3A4_HUMAN Cytochrome P450 3A4 (EC 1.14.13.67) ALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFD MECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIA EDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSM DVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVF PREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSII FIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVN ETLRLFPIAMRLERVCKKDVEINGMFIPKGWVVMIPSYALHRDPKYWTEPEKFLPERFSK KNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGG LLQPEKPVVLKVESRDGTVSGA

Drug Target 1 [top]

Target 1 ID

847

Target 1 Name

Mu-type opioid receptor

Target 1 Synonyms

MOR-1

Target 1 Gene Name

OPRM1

Target 1 Protein Sequence

>Mu-type opioid receptor

MDSSAAPTNASNCTDALAYSSCSPAPSPGSWVNLSHLDGNLSDPCGPNRTDLGGRDSLCP
PTGSPSMITAITIMALYSIVCVVGLFGNFLVMYVIVRYTKMKTATNIYIFNLALADALAT
STLPFQSVNYLMGTWPFGTILCKIVISIDYYNMFTSIFTLCTMSVDRYIAVCHPVKALDF
RTPRNAKIINVCNWILSSAIGLPVMFMATTKYRQGSIDCTLTFSHPTWYWENLLKICVFI
FAFIMPVLIITVCYGLMILRLKSVRMLSGSKEKDRNLRRITRMVLVVVAVFIVCWTPIHI
YVIIKALVTIPETTFQTVSWHFCIALGYTNSCLNPVLYAFLDENFKRCFREFCIPTSSNI
EQQNSTRIRQNTRDHPSTANTVDRTNHQLENLEAETAPLP

Target 1 Number of Residues

406

Target 1 Molecular Weight

44780

Target 1 Theoretical pI

8.29

Target 1 GO Classification

Function
peptide receptor activity, G-protein coupled opioid receptor activity mu-opioid receptor activity signal transducer activity receptor activity transmembrane receptor activity G-protein coupled receptor activity rhodopsin-like receptor activity
Process
cellular process cell communication signal transduction cell surface receptor linked signal transduction G-protein coupled receptor protein signaling pathway
Component
cell membrane intrinsic to membrane integral to membrane

Target 1 General Function

Involved in rhodopsin-like receptor activity

Target 1 Specific Function

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

Target 1 Pathways

Not Available

Target 1 Reactions

Not Available

Target 1 Pfam Domain Function

7tm_1 (PF00001 )

Target 1 Signals

None

Target 1 Transmembrane Regions

67-96
106-123
146-165
196-211
237-259
283-305
314-330

Target 1 Essentiality

Non-Essential

Target 1 GenBank ID Protein

452073

Target 1 UniProtKB/Swiss-Prot ID

P35372

Target 1 UniProtKB/Swiss-Prot Entry Name

OPRM_HUMAN Link Image

Target 1 PDB ID

Not Available

Target 1 Cellular Location

Membrane
multi-pass membrane protein

Target 1 Gene Sequence

>1203 bp

ATGGACAGCAGCGCTGCCCCCACGAACGCCAGCAATTGCACTGATGCCTTGGCGTACTCA
AGTTGCTCCCCAGCACCCAGCCCCGGTTCCTGGGTCAACTTGTCCCACTTAGATGGCAAC
CTGTCCGACCCATGCGGTCCGAACCGCACCAACCTGGGCGGGAGAGACAGCCTGTGCCCT
CCGACCGGCAGTCCCTCCATGATCACGGCCATCACGATCATGGCCCTCTACTCCATCGTG
TGCGTGGTGGGGCTCTTCGGAAACTTCCTGGTCATGTATGTGATTGTCAGATACACCAAG
ATGAAGACTGCCACCAACATCTACATTTTCAACCTTGCTCTGGCAGATGCCTTAGCCACC
AGTACCCTGCCCTTCCAGAGTGTGAATTACCTAATGGGAACATGGCCATTTGGAACCATC
CTTTGCAAGATAGTGATCTCCATAGATTACTATAACATGTTCACCAGCATATTCACCCTC
TGCACCATGAGTGTTGATCGATACATTGCAGTCTGCCACCCTGTCAAGGCCTTAGATTTC
CGTACTCCCCGAAATGCCAAAATTATCAATGTCTGCAACTGGATCCTCTCTTCAGCCATT
GGTCTTCCTGTAATGTTCATGGCTACAACAAAATACAGGCAAGGTTCCATAGATTGTACA
CTAACATTCTCTCATCCAACCTGGTACTGGGAAAACCTCGTGAAGATCTGTGTTTTCATC
TTCGCCTTCATTATGCCAGTGCTCATCATTACCGTGTGCTATGGACTGATGATCTTGCGC
CTCAAGAGTGTCCGCATGCTCTCTGGCTCCAAAGAAAAGGACAGGAATCTTCGAAGGATC
ACCAGGATGGTGCTGGTGGTGGTGGCTGTGTTCATCGTCTGCTGGACTCCCATTCACATT
TACGTCATCATTAAAGCCTTGGTTACAATCCCAGAAACTACGTTCCAGACTGTTTCTTGG
CACTTCTGCATTGCTCTAGGTTACACAAACAGCTGCCTCAACCCAGTCCTTTATGCATTT
CTGGATGAAAACTTCAAACGATGCTTCAGAGAGTTCTGTATCCCAACCTCTTCCAACATT
GAGCAACAAAACTCCACTCGAATTCGTCAGAACACTAGAGACCACCCCTCCACGGCCAAT
ACAGTGGATAGAACTAATCATCAGCTAGAAAATCTGGAAGCAGAAACTGCTCCGTTGCCC
TAA

Target 1 GenBank Gene ID

Target 1 GeneCard ID

OPRM1

Target 1 GenAtlas ID

OPRM1

Target 1 HGNC ID

HGNC:8156

Target 1 Chromosome Location

Target 1 Locus

6q24-q25

Target 1 SNPs

SNPJam Report Link Image

Target 1 General References

Uhl GR, Sora I, Wang Z: The mu opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception, and opiate responses. Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):7752-5. [PubMed ]
Chuang TK, Killam KF Jr, Chuang LF, Kung HF, Sheng WS, Chao CC, Yu L, Chuang RY: Mu opioid receptor gene expression in immune cells. Biochem Biophys Res Commun. 1995 Nov 22;216(3):922-30. [PubMed ]
Mestek A, Hurley JH, Bye LS, Campbell AD, Chen Y, Tian M, Liu J, Schulman H, Yu L: The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C. J Neurosci. 1995 Mar;15(3 Pt 2):2396-406. [PubMed ]
Wang JB, Johnson PS, Persico AM, Hawkins AL, Griffin CA, Uhl GR: Human mu opiate receptor. cDNA and genomic clones, pharmacologic characterization and chromosomal assignment. FEBS Lett. 1994 Jan 31;338(2):217-22. [PubMed ]
Bare LA, Mansson E, Yang D: Expression of two variants of the human mu opioid receptor mRNA in SK-N-SH cells and human brain. FEBS Lett. 1994 Nov 7;354(2):213-6. [PubMed ]
Bergen AW, Kokoszka J, Peterson R, Long JC, Virkkunen M, Linnoila M, Goldman D: Mu opioid receptor gene variants: lack of association with alcohol dependence. Mol Psychiatry. 1997 Oct-Nov;2(6):490-4. [PubMed ]
Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, Gong J, Schluger J, Strong JA, Leal SM, Tischfield JA, Kreek MJ, Yu L: Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9608-13. [PubMed ]

Target 1 Drug References

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 ]
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 ]
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 ]

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.