Tmic
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Record Information
Version2.0
Creation Date2009-07-21 20:28:32 UTC
Update Date2014-12-24 20:25:55 UTC
Accession NumberT3D3006
Identification
Common NamePhenobarbital
ClassSmall Molecule
DescriptionPhenobarbital is only found in individuals that have used or taken this drug. It is a barbituric acid derivative that acts as a nonselective central nervous system depressant. It promotes binding to inhibitory gamma-aminobutyric acid subtype receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. [PubChem] Phenobarbital acts on GABAA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal.
Compound Type
  • Amide
  • Amine
  • Anticonvulsant
  • Drug
  • Excitatory Amino Acid Antagonist
  • GABA Modulator
  • Hypnotic and Sedative
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
5-ethyl-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione
5-Ethyl-5-phenyl-pyrimidine-2,4,6-trione
5-Ethyl-5-phenylbarbituric acid
5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione
5-Phenyl-5-ethylbarbituric acid
Fenobarbital
Luminal
Phenobarbitol
Phenobarbitone
Phenobarbituric acid
Phenylaethylbarbitursaeure
Phenylethylbarbiturate
Phenylethylbarbituric acid
Phenylethylbarbitursaeure
Phenylethylmalonylurea
Chemical FormulaC12H12N2O3
Average Molecular Mass232.235 g/mol
Monoisotopic Mass232.085 g/mol
CAS Registry Number50-06-6
IUPAC Name5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione
Traditional Namephenobarbital
SMILESCCC1(C(O)=NC(=O)N=C1O)C1=CC=CC=C1
InChI IdentifierInChI=1S/C12H12N2O3/c1-2-12(8-6-4-3-5-7-8)9(15)13-11(17)14-10(12)16/h3-7H,2H2,1H3,(H2,13,14,15,16,17)
InChI KeyInChIKey=DDBREPKUVSBGFI-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as barbituric acid derivatives. Barbituric acid derivatives are compounds containing a perhydropyrimidine ring substituted at C-2, -4 and -6 by oxo groups.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazines
Sub ClassPyrimidines and pyrimidine derivatives
Direct ParentBarbituric acid derivatives
Alternative Parents
Substituents
  • Barbiturate
  • Ureide
  • N-acyl urea
  • Monocyclic benzene moiety
  • 1,3-diazinane
  • Benzenoid
  • Dicarboximide
  • Urea
  • Carbonic acid derivative
  • Carboxylic acid derivative
  • Azacycle
  • Organic nitrogen compound
  • Organonitrogen compound
  • Organooxygen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Carbonyl group
  • Organic oxygen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Kidney
  • Liver
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point174°C
Boiling PointNot Available
Solubility1110 mg/L (at 25°C)
LogP1.47
Predicted Properties
PropertyValueSource
Water Solubility0.28 g/LALOGPS
logP1.4ALOGPS
logP1.41ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)7.14ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area75.27 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity59.75 m³·mol⁻¹ChemAxon
Polarizability22.62 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0udi-5970000000-7bda34bd3bb88b5fd9fdView in MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-001i-0090000000-55265fc1e12027dc6454View in MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0udi-5970000000-7bda34bd3bb88b5fd9fdView in MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-001i-0090000000-55265fc1e12027dc6454View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-014i-1940000000-8377cca722b6479ce2fdView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-001i-0190000000-8cf53cd66a890256ea98View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-001i-1290000000-73d0e0b25f99ffc6a500View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0016-3950000000-ab62a9483b8a2a65b563View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0006-0900000000-4121e8dd703c01c1161cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0006-0900000000-4976dfc244184e5d627bView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-001i-1890000000-a12eb2be0b05b9f234deView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03di-1920000000-43ed71cd16bfceef49e6View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-08fr-2900000000-236ae1dab83b15539a86View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-053u-3900000000-2a994f0e45c022cca640View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-053u-4900000000-066a53ca113150f58406View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-05o3-6900000000-b8f9c9d0f71b6d2c6c2fView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0uy3-8900000000-6bcd457bfff85f05fe9cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0udi-9500000000-0ecfff7e43e9e78d677eView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0uxs-9300000000-7413ad1c764a1ae4a98eView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-0190000000-f722d696dc84bd92f7d2View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-03xr-0910000000-d76f47fd3df15d7ea214View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014l-8910000000-29ca3dd7066d66bd0412View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0016-9670000000-ddcdac3a0cb816b2307cView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0006-9610000000-315a80c916d24f8b59e8View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-000x-9700000000-e2564ed7f0e6acd73e7bView in MoNA
MSMass Spectrum (Electron Ionization)splash10-0uxr-6950000000-193bf296d3e5d1705628View in MoNA
1D NMR1H NMR SpectrumNot AvailableView in JSpectraViewer
1D NMR13C NMR SpectrumNot AvailableView in JSpectraViewer
Toxicity Profile
Route of ExposureAbsorbed in varying degrees following oral, rectal or parenteral administration. The salts are more rapidly absorbed than are the acids. The rate of absorption is increased if the sodium salt is ingested as a dilute solution or taken on an empty stomach.
Mechanism of ToxicityPhenobarbital acts on GABAA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal.
MetabolismHepatic (mostly via CYP2C19). Half Life: 53 to 118 hours (mean 79 hours)
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)2B, possibly carcinogenic to humans. (7)
Uses/SourcesFor the treatment of all types of seizures except absence seizures.
Minimum Risk LevelNot Available
Health EffectsThey cause slurred speech, disorientation and "drunken" behavior. They are physically and psychologically addictive. May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.
SymptomsCNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may wshow paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur.
TreatmentTreatment of overdosage is mainly supportive and consists of maintaining an adequate airway with assisted respiration and oxygen administration as necessary, as well as monitoring of vital signs and fluid balance. If the patient is conscious and has not lost the gag reflex, emesis may be induced with ipecac. Care should be taken to prevent pulmonary aspiration of vomitus. After completion of vomiting, 30 grams activated charcoal in a glass of water may be administered. If emesis is contraindicated, gastric lavage may be performed with a cuffed endotracheal tube in place with the patient in the face down position. Activated charcoal may be left in the emptied stomach and a saline cathartic administered. Fluid therapy and other standard treatment for shock should be performed if needed. If renal function is normal, forced diuresis may aid in the elimination of the barbiturate. Alkalinization of the urine increases renal excretion of some barbiturates, especially phenobarbital, also aprobarbital, and mephobarbital (which is metabolized to phenobarbital). Although not recommended as a routine procedure, hemodialysis may be used in severe barbiturate intoxications or if the patient is anuric or in shock. Patient should be rolled from side to side every 30 minutes, and antibiotics should be given if pneumonia is suspected. Appropriate nursing care to prevent hypostatic pneumonia, decubiti, aspiration and other complications of patients with altered states of consciousness should also be performed. (6)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01174
HMDB IDHMDB15305
PubChem Compound ID4763
ChEMBL IDCHEMBL40
ChemSpider ID4599
KEGG IDC07434
UniProt IDNot Available
OMIM ID
ChEBI ID8069
BioCyc IDNot Available
CTD IDNot Available
Stitch IDPhenobarbital
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkPhenobarbital
References
Synthesis Reference

Tong Sun, Shawn Watson, Rajesh Manchanda, “PHENOBARBITAL SALTS; METHODS OF MAKING; AND METHODS OF USE THEREOF.” U.S. Patent US20100035904, issued February 11, 2010.

MSDSLink
General References
  1. Kwan P, Brodie MJ: Phenobarbital for the treatment of epilepsy in the 21st century: a critical review. Epilepsia. 2004 Sep;45(9):1141-9. [15329080 ]
  2. Taylor S, Tudur Smith C, Williamson PR, Marson AG: Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev. 2001;(4):CD002217. [11687150 ]
  3. Tudur Smith C, Marson AG, Williamson PR: Carbamazepine versus phenobarbitone monotherapy for epilepsy. Cochrane Database Syst Rev. 2003;(1):CD001904. [12535420 ]
  4. Kalviainen R, Eriksson K, Parviainen I: Refractory generalised convulsive status epilepticus : a guide to treatment. CNS Drugs. 2005;19(9):759-68. [16142991 ]
  5. Booth D, Evans DJ: Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004218. [15495087 ]
  6. RxList: The Internet Drug Index (2009). [Link]
  7. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Ionotropic glutamate receptor activity
Specific Function:
Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.
Gene Name:
GRIA2
Uniprot ID:
P42262
Molecular Weight:
98820.32 Da
References
  1. Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [11264449 ]
  2. Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [10487207 ]
  3. Jin LJ, Schlesinger F, Song YP, Dengler R, Krampfl K: The interaction of the neuroprotective compounds riluzole and phenobarbital with AMPA-type glutamate receptors: a patch-clamp study. Pharmacology. 2010;85(1):54-62. doi: 10.1159/000268641. Epub 2009 Dec 23. [20051697 ]
General Function:
Ligand-gated ion channel activity
Specific Function:
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions.
Gene Name:
CHRNA4
Uniprot ID:
P43681
Molecular Weight:
69956.47 Da
References
  1. Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [11264449 ]
  2. Arias HR, Bhumireddy P: Anesthetics as chemical tools to study the structure and function of nicotinic acetylcholine receptors. Curr Protein Pept Sci. 2005 Oct;6(5):451-72. [16248797 ]
  3. Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [10487207 ]
General Function:
Toxic substance binding
Specific Function:
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is blocked by alpha-bungarotoxin.
Gene Name:
CHRNA7
Uniprot ID:
P36544
Molecular Weight:
56448.925 Da
References
  1. Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [11264449 ]
  2. Arias HR, Bhumireddy P: Anesthetics as chemical tools to study the structure and function of nicotinic acetylcholine receptors. Curr Protein Pept Sci. 2005 Oct;6(5):451-72. [16248797 ]
  3. Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [10487207 ]
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel (By similarity).
Gene Name:
GABRA1
Uniprot ID:
P14867
Molecular Weight:
51801.395 Da
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 ]
General Function:
Kainate selective glutamate receptor activity
Specific Function:
Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus. Modulates cell surface expression of NETO2 (By similarity).
Gene Name:
GRIK2
Uniprot ID:
Q13002
Molecular Weight:
102582.475 Da
References
  1. Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [11264449 ]
  2. Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [10487207 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Gene Name:
NR1I2
Uniprot ID:
O75469
Molecular Weight:
49761.245 Da
References
  1. Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58. [14977870 ]
  2. Kobayashi K, Yamagami S, Higuchi T, Hosokawa M, Chiba K: Key structural features of ligands for activation of human pregnane X receptor. Drug Metab Dispos. 2004 Apr;32(4):468-72. [15039302 ]
General Function:
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function:
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular Weight:
126653.52 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC503000 uMNot AvailableBindingDB 50021437
IC503019.95172 uMNot AvailableBindingDB 50021437
References
  1. Du LP, Tsai KC, Li MY, You QD, Xia L: The pharmacophore hypotheses of I(Kr) potassium channel blockers: novel class III antiarrhythmic agents. Bioorg Med Chem Lett. 2004 Sep 20;14(18):4771-7. [15324906 ]
  2. Coi A, Massarelli I, Testai L, Calderone V, Bianucci AM: Identification of "toxicophoric" features for predicting drug-induced QT interval prolongation. Eur J Med Chem. 2008 Nov;43(11):2479-88. doi: 10.1016/j.ejmech.2007.12.025. Epub 2008 Jan 5. [18262683 ]
8. NMDA receptor (Protein Group)
General Function:
Voltage-gated cation channel activity
Specific Function:
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors (By similarity).
Included Proteins:
Q05586 , Q12879 , Q13224 , Q14957 , O15399 , Q8TCU5 , O60391
References
  1. Daniell LC: Effect of anesthetic and convulsant barbiturates on N-methyl-D-aspartate receptor-mediated calcium flux in brain membrane vesicles. Pharmacology. 1994 Nov;49(5):296-307. [7862741 ]
General Function:
Voltage-gated sodium channel activity
Specific Function:
Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.
Gene Name:
SCN3A
Uniprot ID:
Q9NY46
Molecular Weight:
226291.905 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>10 uMNot AvailableBindingDB 50021437
References
  1. Waters JA, Hollingsworth EB, Daly JW, Lewandowski G, Creveling CR: Anticonvulsant activity of piperidinol and (dialkylamino)alkanol esters. J Med Chem. 1986 Aug;29(8):1512-6. [3016269 ]