Butorphanol (T3D2837)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (3)XML
Targets (3)
Record Information
Version2.0
Creation Date2009-07-21 20:27:15 UTC
Update Date2014-12-24 20:25:52 UTC
Accession NumberT3D2837
Identification
Common NameButorphanol
ClassSmall Molecule
DescriptionButorphanol is only found in individuals that have used or taken this drug. It is a synthetic morphinan analgesic with narcotic antagonist action. It is used in the management of severe pain. [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. Butorphanol is a mixed agonist-antagonist that exerts antagonistic or partially antagonistic effects at mu opiate receptor sites, but is thought to exert its agonistic effects principally at the kappa and sigma opiate receptors.
Compound Type
  • Amine
  • Analgesic, Opioid
  • Antitussive Agent
  • Drug
  • Metabolite
  • Narcotic
  • Narcotic Antagonist
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDF3D-SDFPDBSMILESInChI View 3D Structure
Synonyms
Synonym
(-)-17-(Cyclobutylmethyl)morphinan-3,14-diol
(-)-Butorphanol
(-)-N-Cyclobutylmethyl-3,14-dihydroxymorphinan
Butaro
Butorfanol
Butorphanol Tartrate
Butorphanolum
Butrum
Stadol
Stadol NS
Chemical FormulaC21H29NO2
Average Molecular Mass327.461 g/mol
Monoisotopic Mass327.220 g/mol
CAS Registry Number42408-82-2
IUPAC Name(1S,9R,10S)-17-(cyclobutylmethyl)-17-azatetracyclo[7.5.3.0¹,¹⁰.0²,⁷]heptadeca-2(7),3,5-triene-4,10-diol
Traditional Namebutorphanol
SMILES[H][C@@]12CC3=C(C=C(O)C=C3)[C@]3(CCCC[C@@]13O)CCN2CC1CCC1
InChI IdentifierInChI=1S/C21H29NO2/c23-17-7-6-16-12-19-21(24)9-2-1-8-20(21,18(16)13-17)10-11-22(19)14-15-4-3-5-15/h6-7,13,15,19,23-24H,1-5,8-12,14H2/t19-,20+,21-/m1/s1
InChI KeyInChIKey=IFKLAQQSCNILHL-QHAWAJNXSA-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
  • Benzazocine
  • Tetralin
  • 1-hydroxy-2-unsubstituted benzenoid
  • Aralkylamine
  • Piperidine
  • Cyclic alcohol
  • Tertiary alcohol
  • 1,2-aminoalcohol
  • Tertiary amine
  • Tertiary aliphatic amine
  • Azacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Organopnictogen compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxygen compound
  • Amine
  • Organic nitrogen compound
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point272-274°C
Boiling PointNot Available
SolubilityModerate
LogP3.3
Predicted Properties
PropertyValueSource
Water Solubility0.16 g/LALOGPS
logP3.65ALOGPS
logP2.89ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)9.86ChemAxon
pKa (Strongest Basic)10.7ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area43.7 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity95.92 m³·mol⁻¹ChemAxon
Polarizability37.94 ųChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-05c5-4090000000-ff08db00ae2474f6b4a52017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-0a4i-6004900000-19e8948f63ea068f317c2017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_2) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_2_1) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS ("Butorphanol,1TMS,#2" TMS) - 70eV, PositiveNot Available2021-10-14View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0400-3009000000-2dca83671d56d098a9c92017-07-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-02t9-9024000000-f37bfb8ff0e2cf9171552017-07-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014i-9000000000-b3868f9e593caf3b586b2017-07-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0029000000-d2856cd83df5e8d33b652017-07-26View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a6r-2098000000-a2f7eacf8c80072ad5b62017-07-26View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4l-4090000000-37ed14b31b49d21947002017-07-26View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-004i-0009000000-8ed73bd9ae49e58d578e2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-004i-0009000000-3cb1bcbf15b91d40d3a02021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-017l-5094000000-f351e63d912694f61c8f2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0009000000-ad4847b3b72e4c91ee0a2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-0009000000-ad4847b3b72e4c91ee0a2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0ab9-1957000000-6d5cd344c3106be1f9e22021-10-11View Spectrum
Toxicity Profile
Route of ExposureRapidly absorbed after intramuscular injection and peak plasma levels are reached in 20-40 minutes. The absolute bioavailability is 60-70% and is unchanged in patients with allergic rhinitis. In patients using a nasal vasoconstrictor (oxymetazoline) the fraction of the dose absorbed was unchanged, but the rate of absorption was slowed. Oral bioavailability is only 5-17% because of extensive first-pass metabolism.
Mechanism of ToxicityThe 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. Butorphanol is a mixed agonist-antagonist that exerts antagonistic or partially antagonistic effects at mu opiate receptor sites, but is thought to exert its agonistic effects principally at the kappa and sigma opiate receptors. Its interactions with these receptors in the central nervous system apparently mediate most of its pharmacologic effects, including analgesia.
MetabolismExtensively metabolized in the liver. The pharmacological activity of butorphanol metabolites has not been studied in humans; in animal studies, butorphanol metabolites have demonstrated some analgesic activity. Route of Elimination: Butorphanol is extensively metabolized in the liver. Elimination occurs by urine and fecal excretion. Half Life: The elimination half-life of butorphanol is about 18 hours. In renally impaired patients with creatinine clearances <30 mL/min the elimination half-life is approximately doubled. After intravenous administration to patients with hepatic impairment, the elimination half-life of butorphanol was approximately tripled.
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesThe most common indication for butorphanol is management of migraine using the intranasal spray formulation. It may also be used parenterally for management of moderate-to-severe pain, as a supplement for balanced general anesthesia, and management of pain during labor. Butorphanol is more effective in reducing pain in women than in men. In veterinary use, butorphanol ("Torbugesic") is widely used as a sedative and analgesic in dogs, cats and horses. [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.
SymptomsThe clinical manifestations of butorphanol overdose are those of opioid drugs in general. The most serious symptoms are hypoventilation, cardiovascular insufficiency, coma, and death. Medical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.
TreatmentThe management of suspected butorphanol overdosage includes maintenance of adequate ventilation, peripheral perfusion, normal body temperature, and protection of the airway. Patients should be under continuous observation with adequate serial measures of mental state, responsiveness, and vital signs. Oxygen and ventilatory assistance should be available with continual monitoring by pulse oximetry if indicated. In the presence of coma, placement of an artificial airway may be required. An adequate intravenous portal should be maintained to facilitate treatment of hypotension associated with vasodilation. The use of a specific opioid antagonist such as naloxone should be considered. As the duration of butorphanol action usually exceeds the duration of action of naloxone, repeated dosing with naloxone may be required. (3)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00611
HMDB IDHMDB14749
PubChem Compound ID6916249
ChEMBL IDCHEMBL33986
ChemSpider ID4514667
KEGG IDC06863
UniProt IDNot Available
OMIM ID
ChEBI ID3242
BioCyc IDNot Available
CTD IDNot Available
Stitch IDButorphanol
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkButorphanol
References
Synthesis Reference

Monkovic, I. and Conway, T.T.; U.S. Patent 3,775,414; November 27,1973; Monkovic, I.,Wong, H. and Lim, G.; U.S. Patent 3,980,641; September 14, 1976; Pachter, IJ., Belleau, B.R. and Monkovic, I.; U.S. Patent 3,819,635; June 25,1974; and Lim, G. and Hooper, J.W.; U.S. Patent 4,017,497; April 12,1977; all assigned to Bristol-Myers Company.

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. Fan LW, Tanaka S, Tien LT, Ma T, Rockhold RW, Ho IK: Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain. Brain Res Bull. 2002 Jun;58(2):149-60. [12127012 ]
  3. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot 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
TypeValueAssay TypeAssay Source
Inhibitory0.00012 uMNot AvailableBindingDB 50240437
Inhibitory0.00022 uMNot AvailableBindingDB 50240437
IC500.014 uMNot AvailableBindingDB 50240437
References
  1. Picker MJ, Benyas S, Horwitz JA, Thompson K, Mathewson C, Smith MA: Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists. J Pharmacol Exp Ther. 1996 Dec;279(3):1130-41. [8968334 ]
  2. Wakabayashi H, Tokuyama S, Ho IK: Simultaneous measurement of biogenic amines and their metabolites in rat brain regions after acute administration of and abrupt withdrawal from butorphanol or morphine. Neurochem Res. 1995 Oct;20(10):1179-85. [8746803 ]
  3. Oh KW, Makimura M, Jaw SP, Hoskins B, Ho IK: Effects of beta-funaltrexamine on butorphanol dependence. Pharmacol Biochem Behav. 1992 May;42(1):29-34. [1528943 ]
  4. 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 ]
  5. Narita M, Feng Y, Makimura M, Hoskins B, Ho IK: Repeated administration of opioids alters characteristics of membrane-bound phorbol ester binding in rat brain. Eur J Pharmacol. 1994 Dec 27;271(2-3):547-50. [7705457 ]
  6. Wentland MP, Lou R, Lu Q, Bu Y, VanAlstine MA, Cohen DJ, Bidlack JM: Syntheses and opioid receptor binding properties of carboxamido-substituted opioids. Bioorg Med Chem Lett. 2009 Jan 1;19(1):203-8. doi: 10.1016/j.bmcl.2008.10.134. Epub 2008 Nov 7. [19027293 ]
  7. 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 ]
  8. Zhang B, Zhang T, Sromek AW, Scrimale T, Bidlack JM, Neumeyer JL: Synthesis and binding affinity of novel mono- and bivalent morphinan ligands for kappa, mu, and delta opioid receptors. Bioorg Med Chem. 2011 May 1;19(9):2808-16. doi: 10.1016/j.bmc.2011.03.052. Epub 2011 Mar 26. [21482470 ]
Target Details
2. 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
References
  1. Vivian JA, DeYoung MB, Sumpter TL, Traynor JR, Lewis JW, Woods JH: kappa-Opioid receptor effects of butorphanol in rhesus monkeys. J Pharmacol Exp Ther. 1999 Jul;290(1):259-65. [10381785 ]
  2. Park Y, Jang CG, Ho IK, Ko KH: kappa-opioid agonist stimulated regional distribution of [(35)S]GTPgammas binding in butorphanol continuously infused rat. Brain Res Bull. 2000 May 1;52(1):17-20. [10779697 ]
  3. Fan LW, Tanaka S, Tien LT, Ma T, Rockhold RW, Ho IK: Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain. Brain Res Bull. 2002 Jun;58(2):149-60. [12127012 ]
  4. Fan LW, Tanaka S, Park Y, Sasaki K, Ma T, Tien LT, Rockhold RW, Ho IK: Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid receptor binding. Brain Res. 2002 Dec 27;958(2):277-90. [12470863 ]
  5. Commiskey S, Fan LW, Ho IK, Rockhold RW: Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci. 2005 Jun;98(2):109-16. Epub 2005 Jun 8. [15942128 ]
Target Details
3. 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
TypeValueAssay TypeAssay Source
Inhibitory0.00012 uMNot AvailableBindingDB 50240437
Inhibitory0.00022 uMNot AvailableBindingDB 50240437
References
  1. Ohta S, Niwa M, Nozaki M, Tsurumi K, Shimonaka H, Tanahashi T, Uematsu H, Yamamoto M, Fujimura H: [Kappa-type opioid receptor in human placental membrane]. Masui. 1989 Oct;38(10):1293-300. [2555580 ]
  2. 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 ]
  3. Zhang B, Zhang T, Sromek AW, Scrimale T, Bidlack JM, Neumeyer JL: Synthesis and binding affinity of novel mono- and bivalent morphinan ligands for kappa, mu, and delta opioid receptors. Bioorg Med Chem. 2011 May 1;19(9):2808-16. doi: 10.1016/j.bmc.2011.03.052. Epub 2011 Mar 26. [21482470 ]
  4. Wentland MP, Lou R, Lu Q, Bu Y, VanAlstine MA, Cohen DJ, Bidlack JM: Syntheses and opioid receptor binding properties of carboxamido-substituted opioids. Bioorg Med Chem Lett. 2009 Jan 1;19(1):203-8. doi: 10.1016/j.bmcl.2008.10.134. Epub 2008 Nov 7. [19027293 ]