T3DB: Nalbuphine

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (3)XML

Targets (3)

Record Information

Version

2.0

Creation Date

2009-07-21 20:27:48 UTC

Update Date

2014-12-24 20:25:53 UTC

Accession Number

T3D2911

Identification

Common Name

Nalbuphine

Class

Small Molecule

Description

Nalbuphine 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

MOL SDF 3D-SDF PDB SMILES InChI View 3D Structure

Synonyms

Synonym
Mexifen
N-Cyclobutylmethyl-4,5alpha-epoxy-3,6alpha,14-morphinantriol
Nalbufina
Nalbuphin
Nalbuphinum
Nalpain
Nubain

Chemical Formula

C₂₁H₂₇NO₄

Average Molecular Mass

357.443 g/mol

Monoisotopic Mass

357.194 g/mol

CAS Registry Number

20594-83-6

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 Name

nalbuphine

SMILES

[H][C@@]12OC3=C(O)C=CC4=C3[C@@]11CCN(CC3CCC3)[C@]([H])(C4)[C@]1(O)CC[C@]2([H])O

InChI Identifier

InChI=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 Key

InChIKey=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.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Phenanthrenes and derivatives

Sub Class

Not Available

Direct Parent

Phenanthrenes 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 Framework

Aromatic heteropolycyclic compounds

External Descriptors

organic heteropentacyclic compound (CHEBI:7454 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Biological Roles

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	230°C as HCl salt
Boiling Point	Not Available
Solubility	35.5 mg/mL at 25°C as HCl salt
LogP	1.4

Predicted Properties

Property	Value	Source
Water Solubility	2.09 g/L	ALOGPS
logP	2	ALOGPS
logP	1.19	ChemAxon
logS	-2.2	ALOGPS
pKa (Strongest Acidic)	7.45	ChemAxon
pKa (Strongest Basic)	13.75	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	3	ChemAxon
Polar Surface Area	73.16 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	97 m³·mol⁻¹	ChemAxon
Polarizability	38.59 Å³	ChemAxon
Number of Rings	6	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-056u-9024000000-f340950b62bc62155aad	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positive	splash10-0a6r-7200190000-d65993f303318329695e	2017-10-06	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_3) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_2_3) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_3_1) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS ("Nalbuphine,2TMS,#3" TMS) - 70eV, Positive	Not Available	2021-10-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-052f-0019000000-d9843432af7f0b68c123	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-052f-2009000000-ebce756d2f09cd1910ab	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-014i-9007000000-bbd85f5711c7e46af99d	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-014i-9000000000-915ad990f371c4dabcfc	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0a4i-0019000000-540f9874c968fbe7262c	2016-08-04	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-052r-1039000000-aa9a27b2348aafb5a2e8	2016-08-04	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-05g3-3090000000-fe24dd502f436a5787fa	2016-08-04	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0009000000-9957b000ea8c41ed8257	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0a4i-0009000000-f48c8684121f5d183a1c	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0zfr-0019000000-e87bebcd47bdb1e8e0a4	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0a4i-0009000000-66d5ef9d584e1b0274e8	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0a4i-0009000000-66d5ef9d584e1b0274e8	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0a4i-0019000000-3615de25291d9c20f0e3	2021-10-11	View Spectrum

Toxicity Profile

Route of Exposure

Intravenous. 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 Toxicity

Receptor 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 Values

LD50: 1100 mg/kg (Oral, Dog) (2)

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

Nalbuphine 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 Level

Not Available

Health Effects

Medical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.

Symptoms

Symptoms of overdose include primarily sleepiness and mild dysphoria.

Treatment

The 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

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

7454

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Nalbuphine

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Nalbuphine

References

Synthesis Reference

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

MSDS

Link

General References

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 ]
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 ]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Mu-type opioid receptor

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

Type	Value	Assay Type	Assay Source
Inhibitory	0.00089 uM	Not Available	BindingDB 50105085
Inhibitory	0.0016 uM	Not Available	BindingDB 50105085
IC50	0.001 uM	Not Available	BindingDB 50105085
IC50	0.096 uM	Not Available	BindingDB 50105085
IC50	0.11 uM	Not Available	BindingDB 50105085

References

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 ]
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 ]
Hoehe M, Duka T: Opiates increase plasma catecholamines in humans. Psychoneuroendocrinology. 1993;18(2):141-8. [8388112 ]
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 ]
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 ]
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 ]
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 ]
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 ]

Target Details

2. Kappa-type opioid receptor

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

Type	Value	Assay Type	Assay Source
Inhibitory	0.0022 uM	Not Available	BindingDB 50105085
Inhibitory	0.003 uM	Not Available	BindingDB 50105085
Inhibitory	0.0039 uM	Not Available	BindingDB 50105085
IC50	0.083 uM	Not Available	BindingDB 50105085

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
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 ]
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 ]
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 ]
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 ]
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 ]

Target Details

3. Delta-type opioid receptor

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

Type	Value	Assay Type	Assay Source
Inhibitory	1 uM	Not Available	BindingDB 50105085

References

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 ]
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 ]
Asai T: Effects of morphine, nalbuphine and pentazocine on gastric emptying of indigestible solids. Arzneimittelforschung. 1998 Aug;48(8):802-5. [9748706 ]
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 ]

Nalbuphine (T3D2911)

Structure for T3D2911: Nalbuphine

Targets

Binding/Activity Constants

References

Binding/Activity Constants

References

Binding/Activity Constants

References