Tmic
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Record Information
Version2.0
Creation Date2009-07-21 20:27:48 UTC
Update Date2014-12-24 20:25:53 UTC
Accession NumberT3D2911
Identification
Common NameNalbuphine
ClassSmall Molecule
DescriptionNalbuphine is only found in individuals that have used or taken this drug. It is a narcotic used as a pain medication. It appears to be an agonist at kappa opioid receptors and an antagonist or partial agonist at mu opioid receptors. [PubChem]The exact mechanism of action is unknown, but is believed to interact with an opiate receptor site in the CNS (probably in or associated with the limbic system). The opiate antagonistic effect may result from competitive inhibition at the opiate receptor, but may also be a result of other mechanisms. Nalbuphine is thought primarily to be a kappa agonist. It is also a partial mu antagonist analgesic, with some binding to the delta receptor and minimal agonist activity at the sigma receptor.
Compound Type
  • Amine
  • Analgesic, Opioid
  • Drug
  • Ether
  • Metabolite
  • Narcotic
  • Narcotic Antagonist
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Mexifen
N-Cyclobutylmethyl-4,5alpha-epoxy-3,6alpha,14-morphinantriol
Nalbufina
Nalbuphin
Nalbuphinum
Nalpain
Nubain
Chemical FormulaC21H27NO4
Average Molecular Mass357.443 g/mol
Monoisotopic Mass357.194 g/mol
CAS Registry Number20594-83-6
IUPAC Name(1S,5R,13R,14S,17S)-4-(cyclobutylmethyl)-12-oxa-4-azapentacyclo[9.6.1.0¹,¹³.0⁵,¹⁷.0⁷,¹⁸]octadeca-7,9,11(18)-triene-10,14,17-triol
Traditional Namenalbuphine
SMILES[H][C@@]12OC3=C(O)C=CC4=C3[C@@]11CCN(CC3CCC3)[C@]([H])(C4)[C@]1(O)CC[C@]2([H])O
InChI IdentifierInChI=1S/C21H27NO4/c23-14-5-4-13-10-16-21(25)7-6-15(24)19-20(21,17(13)18(14)26-19)8-9-22(16)11-12-2-1-3-12/h4-5,12,15-16,19,23-25H,1-3,6-11H2/t15-,16+,19-,20-,21+/m0/s1
InChI KeyInChIKey=NETZHAKZCGBWSS-CEDHKZHLSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenanthrenes and derivatives. These are polycyclic compounds containing a phenanthrene moiety, which is a tricyclic aromatic compound with three non-linearly fused benzene.
KingdomOrganic compounds
Super ClassBenzenoids
ClassPhenanthrenes and derivatives
Sub ClassNot Available
Direct ParentPhenanthrenes and derivatives
Alternative Parents
Substituents
  • Phenanthrene
  • Tetralin
  • Coumaran
  • 1-hydroxy-2-unsubstituted benzenoid
  • Alkyl aryl ether
  • Aralkylamine
  • Piperidine
  • Cyclic alcohol
  • Tertiary alcohol
  • 1,2-aminoalcohol
  • Secondary alcohol
  • Tertiary aliphatic amine
  • Tertiary amine
  • Ether
  • Oxacycle
  • Polyol
  • Azacycle
  • Organoheterocyclic compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organic nitrogen compound
  • Organopnictogen compound
  • Hydrocarbon derivative
  • Alcohol
  • Organic oxygen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point230°C as HCl salt
Boiling PointNot Available
Solubility35.5 mg/mL at 25°C as HCl salt
LogP1.4
Predicted Properties
PropertyValueSource
Water Solubility2.09 g/LALOGPS
logP2ALOGPS
logP1.19ChemAxon
logS-2.2ALOGPS
pKa (Strongest Acidic)7.45ChemAxon
pKa (Strongest Basic)13.75ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area73.16 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity97 m³·mol⁻¹ChemAxon
Polarizability38.59 ųChemAxon
Number of Rings6ChemAxon
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, Positivesplash10-056u-9024000000-f340950b62bc62155aadView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-0a6r-7200190000-d65993f303318329695eView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-052f-2009000000-ebce756d2f09cd1910abView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-014i-9007000000-bbd85f5711c7e46af99dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014i-9000000000-915ad990f371c4dabcfcView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0019000000-540f9874c968fbe7262cView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-052r-1039000000-aa9a27b2348aafb5a2e8View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-05g3-3090000000-fe24dd502f436a5787faView in MoNA
Toxicity Profile
Route of ExposureIntravenous. The mean absolute bioavailability was 81% and 83% for the 10 and 20 mg intramuscular doses, respectively, and 79% and 76% following 10 and 20 mg of subcutaneous nalbuphine.
Mechanism of ToxicityReceptor studies show that nalbuphine exerts its action via binding to mu, kappa, and delta receptors, but not to sigma receptors. Nalbuphine is primarily a kappa agonist/partial mu antagonist analgesic. The exact mechanism of action is unknown, but is believed to interact with an opiate receptor site in the CNS (probably in or associated with the limbic system). The opiate antagonistic effect may result from competitive inhibition at the opiate receptor, but may also be a result of other mechanisms. Nalbuphine is thought primarily to be a kappa agonist. It is also a partial mu antagonist analgesic, with some binding to the delta receptor and minimal agonist activity at the sigma receptor.
Metabolism Half Life: The plasma half-life of nalbuphine is 5 hours, and in clinical studies the duration of analgesic activity has been reported to range from 3 to 6 hours.
Toxicity ValuesLD50: 1100 mg/kg (Oral, Dog) (2)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesNalbuphine is indicated for the relief of moderate to severe pain. It can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery. [Wikipedia]
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.
SymptomsSymptoms of overdose include primarily sleepiness and mild dysphoria.
TreatmentThe immediate intravenous administration an opiate antagonist such as naloxone or nalmefene is a specific antidote. Oxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated. (3)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00844
HMDB IDHMDB14982
PubChem Compound ID5311304
ChEMBL IDCHEMBL895
ChemSpider ID4470813
KEGG IDC07251
UniProt IDNot Available
OMIM ID
ChEBI ID7454
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNalbuphine
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkNalbuphine
References
Synthesis Reference

Michael R. Magruder, “Nalbuphine-narcotic analgesic composition and method of producing analgesia.” U.S. Patent US4366159, issued August, 1981.

MSDSLink
General References
  1. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD: The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain. Pain. 1999 Nov;83(2):339-45. [10534607 ]
  2. 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 ]
  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
Inhibitory0.00089 uMNot AvailableBindingDB 50105085
Inhibitory0.0016 uMNot AvailableBindingDB 50105085
IC500.001 uMNot AvailableBindingDB 50105085
IC500.096 uMNot AvailableBindingDB 50105085
IC500.11 uMNot AvailableBindingDB 50105085
References
  1. Picker MJ: Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine: cross-substitution by mu and delta opioid agonists. J Pharmacol Exp Ther. 1997 Dec;283(3):1009-17. [9399970 ]
  2. Kishioka S, Ko MC, Woods JH: Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys. Eur J Pharmacol. 2000 May 26;397(1):85-92. [10844102 ]
  3. Hoehe M, Duka T: Opiates increase plasma catecholamines in humans. Psychoneuroendocrinology. 1993;18(2):141-8. [8388112 ]
  4. Zernig G, Lewis JW, Woods JH: Clocinnamox inhibits the intravenous self-administration of opioid agonists in rhesus monkeys: comparison with effects on opioid agonist-mediated antinociception. Psychopharmacology (Berl). 1997 Feb;129(3):233-42. [9084061 ]
  5. Chen SL, Huang EY, Chow LH, Tao PL: Dextromethorphan differentially affects opioid antinociception in rats. Br J Pharmacol. 2005 Feb;144(3):400-4. [15655510 ]
  6. Poulain R, Horvath D, Bonnet B, Eckhoff C, Chapelain B, Bodinier MC, Deprez B: From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands. J Med Chem. 2001 Oct 11;44(21):3378-90. [11585443 ]
  7. Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, Ganorkar R, VanAlstine MA, Guo C, Cohen DJ, Bidlack JM: Syntheses of novel high affinity ligands for opioid receptors. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2289-94. doi: 10.1016/j.bmcl.2009.02.078. Epub 2009 Feb 25. [19282177 ]
  8. Peng X, Knapp BI, Bidlack JM, Neumeyer JL: Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors. J Med Chem. 2007 May 3;50(9):2254-8. Epub 2007 Apr 4. [17407276 ]
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
Inhibitory0.0022 uMNot AvailableBindingDB 50105085
Inhibitory0.003 uMNot AvailableBindingDB 50105085
Inhibitory0.0039 uMNot AvailableBindingDB 50105085
IC500.083 uMNot AvailableBindingDB 50105085
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  3. Poulain R, Horvath D, Bonnet B, Eckhoff C, Chapelain B, Bodinier MC, Deprez B: From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands. J Med Chem. 2001 Oct 11;44(21):3378-90. [11585443 ]
  4. Peng X, Knapp BI, Bidlack JM, Neumeyer JL: Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors. J Med Chem. 2007 May 3;50(9):2254-8. Epub 2007 Apr 4. [17407276 ]
  5. Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, Ganorkar R, VanAlstine MA, Guo C, Cohen DJ, Bidlack JM: Syntheses of novel high affinity ligands for opioid receptors. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2289-94. doi: 10.1016/j.bmcl.2009.02.078. Epub 2009 Feb 25. [19282177 ]
  6. Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T: Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol. 1994 Feb;45(2):330-4. [8114680 ]
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
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory1 uMNot AvailableBindingDB 50105085
References
  1. Preston KL, Bigelow GE, Bickel WK, Liebson IA: Drug discrimination in human postaddicts: agonist-antagonist opioids. J Pharmacol Exp Ther. 1989 Jul;250(1):184-96. [2473187 ]
  2. Chen JC, Smith ER, Cahill M, Cohen R, Fishman JB: The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine. Life Sci. 1993;52(4):389-96. [8093631 ]
  3. Asai T: Effects of morphine, nalbuphine and pentazocine on gastric emptying of indigestible solids. Arzneimittelforschung. 1998 Aug;48(8):802-5. [9748706 ]
  4. Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T: Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol. 1994 Feb;45(2):330-4. [8114680 ]