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Hydrocodone (T3D2941)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (3)XML
Targets (3)
Record Information
Version2.0
Creation Date2009-07-21 20:28:02 UTC
Update Date2014-12-24 20:25:53 UTC
Accession NumberT3D2941
Identification
Common NameHydrocodone
ClassSmall Molecule
DescriptionHydrocodone is only found in individuals that have used or taken this drug. It is a narcotic analgesic related to codeine, but more potent and more addicting by weight. It is used also as cough suppressant. [PubChem]Hydrocodone acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Hydrocodone primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, 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 such as hydrocodone also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
Compound Type
  • Amine
  • Analgesic
  • Analgesic, Opioid
  • Antitussive Agent
  • Drug
  • Ether
  • Metabolite
  • Narcotic
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
(-)-Dihydrocodeinone
4,5-alpha-Epoxy-3-methoxy-17-methylmorphinan-6-one
Dihydrocodeinone
Hidrocodona
Hydrocodon
Hydrocodonum
Hydrocone
Hydroconum
Idrocodone
Reprexain
Zohydro
Chemical FormulaC18H21NO3
Average Molecular Mass299.364 g/mol
Monoisotopic Mass299.152 g/mol
CAS Registry Number125-29-1
IUPAC Name(1S,5R,13R,17R)-10-methoxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0¹,¹³.0⁵,¹⁷.0⁷,¹⁸]octadeca-7(18),8,10-trien-14-one
Traditional Namehydrocodone
SMILES[H][C@@]12OC3=C(OC)C=CC4=C3[C@@]11CCN(C)[C@]([H])(C4)[C@]1([H])CCC2=O
InChI IdentifierInChI=1S/C18H21NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3,6,11-12,17H,4-5,7-9H2,1-2H3/t11-,12+,17-,18-/m0/s1
InChI KeyInChIKey=LLPOLZWFYMWNKH-CMKMFDCUSA-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
  • Isoquinolone
  • Tetralin
  • Coumaran
  • Anisole
  • Alkyl aryl ether
  • Aralkylamine
  • Piperidine
  • Benzenoid
  • Ketone
  • Tertiary amine
  • Tertiary aliphatic amine
  • Oxacycle
  • Ether
  • Azacycle
  • Organoheterocyclic compound
  • Amine
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxide
  • Organic nitrogen compound
  • Organopnictogen compound
  • Carbonyl group
  • Organic oxygen compound
  • 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 Point198°C
Boiling PointNot Available
SolubilityInsoluble
LogP1.2
Predicted Properties
PropertyValueSource
Water Solubility0.8 g/LALOGPS
logP2.13ALOGPS
logP1.96ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)18ChemAxon
pKa (Strongest Basic)8.61ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area38.77 ŲChemAxon
Rotatable Bond Count1ChemAxon
Refractivity82.74 m³·mol⁻¹ChemAxon
Polarizability32.05 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, Positivesplash10-0a4i-2090000000-117774746c444c4e04882017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0udi-0009000000-f21858df54194757e2d92017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0udi-0009000000-9b129b5d29df523452722017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0udi-0649000000-82623b23b75f0a0b232d2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0002-0920000000-b67ff5a32d0ddd40c4c72017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-006t-0900000000-0277ba7435a4081ab3332017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0g6v-0900000000-b335c52fad1274cd28cb2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-0udi-0539000000-60e3ee4cd365c32565d22021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 90V, Positivesplash10-0g6v-0900000000-a3ca9b5bf55ce8c114d52021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 45V, Positivesplash10-0udi-0539000000-a9095e27f0dee030ee9a2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-0udi-0009000000-dfe701f042e4ae48fa1d2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 60V, Positivesplash10-0002-0921000000-93f2238f422f7dbee1002021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 75V, Positivesplash10-006t-0900000000-85ee173792972a321cc12021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 15V, Positivesplash10-0udi-0009000000-c527bc2c918e346dafb82021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0udi-0029000000-1c3fa3b4b1357be626162016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0udi-1098000000-f000ea847c9e68994f232016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4i-8090000000-dd4e0e79adfda3b828cc2016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-0090000000-d9ab1faf7327dd439b2c2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0002-0090000000-2b3b1b2934a4489426fc2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-003r-1190000000-666f47c119770568eaf12016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0udi-0009000000-1d8c7ea64ca3af7aef5e2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0udi-0009000000-8b328c7a2ca4dc1b0c722021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0f6x-2091000000-71570a929a535e2fa4d22021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-0090000000-cf6f68fb1a2e8ad8e4162021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0002-0090000000-cf6f68fb1a2e8ad8e4162021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-000t-0090000000-0f770b43a2251fd7dba12021-10-11View Spectrum
MSMass Spectrum (Electron Ionization)splash10-0005-6970000000-3ba3e105098639cd60912014-09-20View Spectrum
Toxicity Profile
Route of ExposureOral. Well absorbed from the gastrointestinal tract.
Mechanism of ToxicityHydrocodone acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Hydrocodone primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, 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 such as hydrocodone also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
MetabolismHepatic and also in intestinal mucosa. Half Life: 1.25-3 hours
Toxicity ValuesLD50: 85.7mg/kg (Parenteral-subcutaneous, Mouse) (1)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor relief of moderate to moderately severe pain. Also used for the symptomatic relief of nonproductive cough, alone or in combination with other antitussives or expectorants.
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 respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, dizziness, ringing in the ears, confusion, blurred vision, eye problems, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdose, apnea, circulatory collapse, cardiac arrest and death may occur.
TreatmentImmediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is alert (adequate pharyngeal and laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying. The first dose should be accompanied by an appropriate cathartic. If repeated doses are used, the cathartic might be included with alternate doses as required. Hypotension is usually hypovolemic and should respond to fluids. Vasopressors and other supportive measures should be employed as indicated. A cuffed endo-tracheal tube should be inserted before gastric lavage of the unconscious patient and, when necessary, to provide assisted respiration. Meticulous attention should be given to maintaining adequate pulmonary ventilation. In severe cases of intoxication, peritoneal dialysis, or preferably hemodialysis may be considered. Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Naloxone hydrochloride 0.4 mg to 2 mg is given parenterally. Since the duration of action of hydrocodone may exceed that of the naloxone, the patient should be kept under continuous surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. (3)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00956
HMDB IDHMDB15091
PubChem Compound ID5284569
ChEMBL IDCHEMBL1457
ChemSpider ID4447623
KEGG IDC08024
UniProt IDNot Available
OMIM ID
ChEBI ID5779
BioCyc IDNot Available
CTD IDNot Available
Stitch IDHydrocodone
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkHydrocodone
References
Synthesis Reference

Anne M. Hailes, Christopher E. French, Neil C. Bruce, “Morphinone reductase for the preparation of hydromorphone and hydrocodone.” U.S. Patent US5571685, issued November, 1990.

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

Target Details
1. 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. Hennies HH, Friderichs E, Schneider J: Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung. 1988 Jul;38(7):877-80. [2849950 ]
  2. Kotzer CJ, Hay DW, Dondio G, Giardina G, Petrillo P, Underwood DC: The antitussive activity of delta-opioid receptor stimulation in guinea pigs. J Pharmacol Exp Ther. 2000 Feb;292(2):803-9. [10640321 ]
  3. McLaughlin JP, Hill KP, Jiang Q, Sebastian A, Archer S, Bidlack JM: Nitrocinnamoyl and chlorocinnamoyl derivatives of dihydrocodeinone: in vivo and in vitro characterization of mu-selective agonist and antagonist activity. J Pharmacol Exp Ther. 1999 Apr;289(1):304-11. [10087018 ]
  4. Cheremina O, Bachmakov I, Neubert A, Brune K, Fromm MF, Hinz B: Simultaneous determination of oxycodone and its major metabolite, noroxycodone, in human plasma by high-performance liquid chromatography. Biomed Chromatogr. 2005 Dec;19(10):777-82. [15920700 ]
  5. Thompson CM, Wojno H, Greiner E, May EL, Rice KC, Selley DE: Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors. J Pharmacol Exp Ther. 2004 Feb;308(2):547-54. Epub 2003 Nov 4. [14600248 ]
Target Details
2. 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
Inhibitory0.0095 uMNot AvailableBindingDB 50386689
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Kotzer CJ, Hay DW, Dondio G, Giardina G, Petrillo P, Underwood DC: The antitussive activity of delta-opioid receptor stimulation in guinea pigs. J Pharmacol Exp Ther. 2000 Feb;292(2):803-9. [10640321 ]
  3. Peckham EM, Traynor JR: Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague-Dawley rats. J Pharmacol Exp Ther. 2006 Mar;316(3):1195-201. Epub 2005 Nov 16. [16291875 ]
  4. McLaughlin JP, Hill KP, Jiang Q, Sebastian A, Archer S, Bidlack JM: Nitrocinnamoyl and chlorocinnamoyl derivatives of dihydrocodeinone: in vivo and in vitro characterization of mu-selective agonist and antagonist activity. J Pharmacol Exp Ther. 1999 Apr;289(1):304-11. [10087018 ]
  5. 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 ]
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
Inhibitory0.26 uMNot AvailableBindingDB 50386689
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. 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 ]