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Record Information
Version2.0
Creation Date2009-07-21 20:27:50 UTC
Update Date2014-12-24 20:25:53 UTC
Accession NumberT3D2914
Identification
Common NameLevorphanol
ClassSmall Molecule
DescriptionLevorphanol is only found in individuals that have used or taken this drug. It is a narcotic analgesic that may be habit-forming. It is nearly as effective orally as by injection. [PubChem]Like other mu-agonist opioids it is believed to act at receptors in the periventricular and periaqueductal gray matter in both the brain and spinal cord to alter the transmission and perception of pain.
Compound Type
  • Amine
  • Analgesic, Opioid
  • Drug
  • Metabolite
  • Narcotic
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Aromarone
Cetarin
Dea No. 9220
Dea No. 9733
Lemoran
Levo-Dromoran
Levorfanol
Levorfanolo
Levorphan
Levorphanal
Lévorphanol
Levorphanol Dl-Form
Levorphanolum
Methorphinan
Racemethorphanum
Chemical FormulaC17H23NO
Average Molecular Mass257.371 g/mol
Monoisotopic Mass257.178 g/mol
CAS Registry Number77-07-6
IUPAC Name(1R,9R,10R)-17-methyl-17-azatetracyclo[7.5.3.0¹,¹⁰.0²,⁷]heptadeca-2(7),3,5-trien-4-ol
Traditional Namelevorphanol
SMILES[H][C@@]12CC3=C(C=C(O)C=C3)[C@]3(CCCC[C@@]13[H])CCN2C
InChI IdentifierInChI=1S/C17H23NO/c1-18-9-8-17-7-3-2-4-14(17)16(18)10-12-5-6-13(19)11-15(12)17/h5-6,11,14,16,19H,2-4,7-10H2,1H3/t14-,16+,17+/m0/s1
InChI KeyInChIKey=JAQUASYNZVUNQP-USXIJHARSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as morphinans. These are polycyclic compounds with a four-ring skeleton with three condensed six-member rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.
KingdomOrganic compounds
Super ClassAlkaloids and derivatives
ClassMorphinans
Sub ClassNot Available
Direct ParentMorphinans
Alternative Parents
Substituents
  • Morphinan
  • Phenanthrene
  • Benzazocine
  • Tetralin
  • 1-hydroxy-2-unsubstituted benzenoid
  • Aralkylamine
  • Piperidine
  • Benzenoid
  • Tertiary aliphatic amine
  • Tertiary amine
  • Organoheterocyclic compound
  • Azacycle
  • Organopnictogen compound
  • Amine
  • Organic oxygen compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point198-199°C
Boiling PointNot Available
Solubility1840 mg/L
LogP3.11
Predicted Properties
PropertyValueSource
Water Solubility0.17 g/LALOGPS
logP3.29ALOGPS
logP2.9ChemAxon
logS-3.2ALOGPS
pKa (Strongest Acidic)10.46ChemAxon
pKa (Strongest Basic)9.66ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area23.47 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity78.08 m³·mol⁻¹ChemAxon
Polarizability29.84 ųChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-00ou-0190000000-14189f3c821f5d9240bfView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-0hbi-2096000000-da9354b628843987f142View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-0090000000-6ba0fc98a8d249fe2da0View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a4i-0090000000-d3e64fd4fd1d790a54bbView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0596-6790000000-7a77fc910d8d984d1012View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0090000000-503f808754310f636373View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-0090000000-bce69f729c40b2f3bed9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-002g-1290000000-97ee80b268d9fa4de679View in MoNA
MSMass Spectrum (Electron Ionization)splash10-0a4i-5930000000-4593c62f1e2a0579a248View in MoNA
Toxicity Profile
Route of ExposureSubcutaneous, Intravenous, or Intramuscular injection ; Oral. Levorphanol is well absorbed after PO administration with peak plasma concentrations occurring approximately 1 hour after dosing.
Mechanism of ToxicityLike other mu-agonist opioids it is believed to act at receptors in the periventricular and periaqueductal gray matter in both the brain and spinal cord to alter the transmission and perception of pain.
MetabolismLevorphanol is extensively metabolized in the liver and is eliminated as the glucuronide metabolite. Half Life: 11-16 hours
Toxicity ValuesLD50: 150 mg/kg (Oral, Rat) (1)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the management of moderate to severe pain or as a preoperative medication where an opioid analgesic is appropriate
Minimum Risk LevelNot Available
Health EffectsMedical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.
SymptomsSigns of overdose include nausea, emesis, dizziness, respiratory depression, hypotension, urinary retention, cardiac arrhythmias, allergic reactions, skin rash, and uticaria.
TreatmentThe specific treatment of suspected levorphanol tartrate overdosage is immediate establishment of an adequate airway and ventilation, followed (if necessary) by intravenous naloxone. The respiratory and cardiac status of the patient should be continuously monitored and appropriate supportive measures instituted, such as oxygen, intravenous fluids and/or vasopressors, if required. Physicians are reminded that the duration of levorphanol action far exceeds the duration of action of naloxone, and repeated dosing with naloxone may be required. Naloxone should be administered cautiously to persons known or suspected to be physically dependent on Levorphanol. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute abstinence syndrome. If necessary to administer naloxone to the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist. (3)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00854
HMDB IDHMDB14992
PubChem Compound ID5359272
ChEMBL IDCHEMBL592
ChemSpider ID16736212
KEGG IDC08014
UniProt IDNot Available
OMIM ID
ChEBI ID119572
BioCyc IDNot Available
CTD IDNot Available
Stitch IDLevorphanol
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkLevorphanol
References
Synthesis Reference

Joseph P. Haar, “Process for the Production of Levorphanol and Related Compounds.” U.S. Patent US20080146805, issued June 19, 2008.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Drugs.com [Link]
  3. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

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 dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling whereas morphine induces only low desensitization and endocytosis. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 12 couples to GNAS and is proposed to be involved in excitatory effects. Isoform 16 and isoform 17 do not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity.
Gene Name:
OPRM1
Uniprot ID:
P35372
Molecular Weight:
44778.855 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.00021 uMNot AvailableBindingDB 50017233
IC500.00013 uMNot AvailableBindingDB 50017233
IC500.0006 uMNot AvailableBindingDB 50017233
IC500.017 uMNot AvailableBindingDB 50017233
References
  1. Allen RM, Granger AL, Dykstra LA: The competitive N-methyl-D-aspartate receptor antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) potentiates the antinociceptive effects of opioids that vary in efficacy at the mu-opioid receptor. J Pharmacol Exp Ther. 2003 Nov;307(2):785-92. Epub 2003 Sep 15. [12975489 ]
  2. Hanessian S, Parthasarathy S, Mauduit M, Payza K: The power of visual imagery in drug design. Isopavines as a new class of morphinomimetics and their human opioid receptor binding activity. J Med Chem. 2003 Jan 2;46(1):34-48. [12502358 ]
  3. Fujimoto RA, Boxer J, Jackson RH, Simke JP, Neale RF, Snowhill EW, Barbaz BJ, Williams M, Sills MA: Synthesis, opioid receptor binding profile, and antinociceptive activity of 1-azaspiro[4.5]decan-10-yl amides. J Med Chem. 1989 Jun;32(6):1259-65. [2542556 ]
  4. DiMaio J, Nguyen TM, Lemieux C, Schiller PW: Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogues: effect of conformational constraints on opiate receptor selectivity. J Med Chem. 1982 Dec;25(12):1432-8. [6296388 ]
  5. Neumeyer JL, Gu XH, van Vliet LA, DeNunzio NJ, Rusovici DE, Cohen DJ, Negus SS, Mello NK, Bidlack JM: Mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan. Bioorg Med Chem Lett. 2001 Oct 22;11(20):2735-40. [11591513 ]
  6. Neumeyer JL, Zhang A, Xiong W, Gu XH, Hilbert JE, Knapp BI, Negus SS, Mello NK, Bidlack JM: Design and synthesis of novel dimeric morphinan ligands for kappa and micro opioid receptors. J Med Chem. 2003 Nov 20;46(24):5162-70. [14613319 ]
  7. Zhang A, Xiong W, Bidlack JM, Hilbert JE, Knapp BI, Wentland MP, Neumeyer JL: 10-Ketomorphinan and 3-substituted-3-desoxymorphinan analogues as mixed kappa and micro opioid ligands: synthesis and biological evaluation of their binding affinity at opioid receptors. J Med Chem. 2004 Jan 1;47(1):165-74. [14695830 ]
  8. Zhang A, Xiong W, Hilbert JE, DeVita EK, Bidlack JM, Neumeyer JL: 2-aminothiazole-derived opioids. Bioisosteric replacement of phenols. J Med Chem. 2004 Apr 8;47(8):1886-8. [15055988 ]
  9. Peng X, Knapp BI, Bidlack JM, Neumeyer JL: Synthesis and preliminary in vitro investigation of bivalent ligands containing homo- and heterodimeric pharmacophores at mu, delta, and kappa opioid receptors. J Med Chem. 2006 Jan 12;49(1):256-62. [16392810 ]
  10. Peng X, Knapp BI, Bidlack JM, Neumeyer JL: High-affinity carbamate analogues of morphinan at opioid receptors. Bioorg Med Chem Lett. 2007 Mar 15;17(6):1508-11. Epub 2007 Jan 17. [17276685 ]
  11. Fulton BS, Knapp BI, Bidlack JM, Neumeyer JL: Synthesis and pharmacological evaluation of hydrophobic esters and ethers of butorphanol at opioid receptors. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4474-6. doi: 10.1016/j.bmcl.2008.07.054. Epub 2008 Jul 17. [18674902 ]
  12. Neumeyer JL, Zhang B, Zhang T, Sromek AW, Knapp BI, Cohen DJ, Bidlack JM: Synthesis, binding affinity, and functional in vitro activity of 3-benzylaminomorphinan and 3-benzylaminomorphine ligands at opioid receptors. J Med Chem. 2012 Apr 26;55(8):3878-90. doi: 10.1021/jm3001086. Epub 2012 Apr 4. [22439881 ]
General Function:
Opioid receptor activity
Specific Function:
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.
Gene Name:
OPRK1
Uniprot ID:
P41145
Molecular Weight:
42644.665 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.0023 uMNot AvailableBindingDB 50017233
IC500.004 uMNot AvailableBindingDB 50017233
References
  1. Prommer E: Levorphanol: the forgotten opioid. Support Care Cancer. 2007 Mar;15(3):259-64. Epub 2006 Oct 13. [17039381 ]
  2. Hanessian S, Parthasarathy S, Mauduit M, Payza K: The power of visual imagery in drug design. Isopavines as a new class of morphinomimetics and their human opioid receptor binding activity. J Med Chem. 2003 Jan 2;46(1):34-48. [12502358 ]
  3. Neumeyer JL, Gu XH, van Vliet LA, DeNunzio NJ, Rusovici DE, Cohen DJ, Negus SS, Mello NK, Bidlack JM: Mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan. Bioorg Med Chem Lett. 2001 Oct 22;11(20):2735-40. [11591513 ]
  4. Neumeyer JL, Zhang A, Xiong W, Gu XH, Hilbert JE, Knapp BI, Negus SS, Mello NK, Bidlack JM: Design and synthesis of novel dimeric morphinan ligands for kappa and micro opioid receptors. J Med Chem. 2003 Nov 20;46(24):5162-70. [14613319 ]
  5. Zhang A, Xiong W, Bidlack JM, Hilbert JE, Knapp BI, Wentland MP, Neumeyer JL: 10-Ketomorphinan and 3-substituted-3-desoxymorphinan analogues as mixed kappa and micro opioid ligands: synthesis and biological evaluation of their binding affinity at opioid receptors. J Med Chem. 2004 Jan 1;47(1):165-74. [14695830 ]
  6. Zhang A, Xiong W, Hilbert JE, DeVita EK, Bidlack JM, Neumeyer JL: 2-aminothiazole-derived opioids. Bioisosteric replacement of phenols. J Med Chem. 2004 Apr 8;47(8):1886-8. [15055988 ]
  7. Peng X, Knapp BI, Bidlack JM, Neumeyer JL: Synthesis and preliminary in vitro investigation of bivalent ligands containing homo- and heterodimeric pharmacophores at mu, delta, and kappa opioid receptors. J Med Chem. 2006 Jan 12;49(1):256-62. [16392810 ]
  8. Peng X, Knapp BI, Bidlack JM, Neumeyer JL: High-affinity carbamate analogues of morphinan at opioid receptors. Bioorg Med Chem Lett. 2007 Mar 15;17(6):1508-11. Epub 2007 Jan 17. [17276685 ]
  9. Fulton BS, Knapp BI, Bidlack JM, Neumeyer JL: Synthesis and pharmacological evaluation of hydrophobic esters and ethers of butorphanol at opioid receptors. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4474-6. doi: 10.1016/j.bmcl.2008.07.054. Epub 2008 Jul 17. [18674902 ]
  10. Neumeyer JL, Zhang B, Zhang T, Sromek AW, Knapp BI, Cohen DJ, Bidlack JM: Synthesis, binding affinity, and functional in vitro activity of 3-benzylaminomorphinan and 3-benzylaminomorphine ligands at opioid receptors. J Med Chem. 2012 Apr 26;55(8):3878-90. doi: 10.1021/jm3001086. Epub 2012 Apr 4. [22439881 ]
General Function:
Opioid receptor activity
Specific Function:
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine.
Gene Name:
OPRD1
Uniprot ID:
P41143
Molecular Weight:
40368.235 Da
References
  1. Prommer E: Levorphanol: the forgotten opioid. Support Care Cancer. 2007 Mar;15(3):259-64. Epub 2006 Oct 13. [17039381 ]