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Identification
NamePicrotoxin
Accession NumberDB00466  (APRD00269)
TypeSmall Molecule
GroupsExperimental
Description

A noncompetitive antagonist at GABA-A receptors and thus a convulsant. Picrotoxin blocks the gamma-aminobutyric acid-activated chloride ionophore. Although it is most often used as a research tool, it has been used as a CNS stimulant and an antidote in poisoning by CNS depressants, especially the barbiturates. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
cocculinNot AvailableIS
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number124-87-8
WeightAverage: 602.5832
Monoisotopic: 602.199941174
Chemical FormulaC30H34O13
InChI KeyVJKUPQSHOVKBCO-ZTYBEOBUSA-N
InChI
InChI=1S/C15H18O7.C15H16O6/c1-12(2,18)6-7-10(16)20-8(6)9-13(3)14(7,19)4-5-15(13,22-5)11(17)21-9;1-5(2)7-8-11(16)19-9(7)10-13(3)14(8,18)4-6-15(13,21-6)12(17)20-10/h5-9,18-19H,4H2,1-3H3;6-10,18H,1,4H2,2-3H3/t5-,6+,7?,8?,9-,13-,14-,15+;6?,7-,8?,9?,10+,13+,14+,15-/m10/s1
IUPAC Name
(1R,3R,5S,8S,13R,14S)-1-hydroxy-14-(2-hydroxypropan-2-yl)-13-methyl-4,7,10-trioxapentacyclo[6.4.1.1⁹,¹².0³,⁵.0⁵,¹³]tetradecane-6,11-dione; (1R,5S,8S,13R,14R)-1-hydroxy-13-methyl-14-(prop-1-en-2-yl)-4,7,10-trioxapentacyclo[6.4.1.1⁹,¹².0³,⁵.0⁵,¹³]tetradecane-6,11-dione
SMILES
[H][C@@]12OC(=O)[C@@]34OC3C[C@@](O)(C3[C@@H](C1OC3=O)C(C)=C)[C@@]24C.[H][C@@]12C[C@@]3(O)C4[C@@H](C(OC4=O)[C@@]4([H])OC(=O)[C@]1(O2)[C@@]34C)C(C)(C)O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as furopyrans. These are organic polycyclic compounds containing a furan ring fused to a pyran ring. Furan is a five-membered aromatic ring with four carbon atoms and one oxygen atom. Pyran a six-membered heterocyclic, non-aromatic ring, made up of five carbon atoms and one oxygen atom and containing two double bonds.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassFuropyrans
Sub ClassNot Available
Direct ParentFuropyrans
Alternative Parents
Substituents
  • Furopyran
  • Caprolactone
  • Oxepane
  • Pyran
  • Oxane
  • Gamma butyrolactone
  • Saccharide
  • Tertiary alcohol
  • Oxolane
  • Furan
  • Cyclic alcohol
  • Lactone
  • Carboxylic acid ester
  • Oxacycle
  • Monocarboxylic acid or derivatives
  • Ether
  • Oxirane
  • Dialkyl ether
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Alcohol
  • Aliphatic heteropolycyclic compound
Molecular FrameworkNot Available
External DescriptorsNot Available
Pharmacology
IndicationUsed internally for relieving respiratory distress. Also for use as an antidote in poisoning by CNS depressants, especially barbiturates.
PharmacodynamicsPicrotoxin is a toxin obtained from the seeds of the shrub Anamirta cocculus. It is used as a central nervous system stimulant, antidote, convulsant, and GABA (gamma aminobutyric acid) antagonist. It is a noncompetitive antagonist at GABAA receptors and thus a convulsant. Picrotoxin blocks the GABAActivated chloride ionophore. Although it is most often used as a research tool, it has been used as a CNS stimulant and an antidote in poisoning by CNS depressants, especially barbiturates.
Mechanism of actionPicrotoxin antagonizes the GABAA receptor channel directly, which is a ligand-gated ion channel concerned chiefly with the passing of chloride ions across the cell membrane. Therefore picrotoxin prevents Cl- channel permeability and thus promtes an inhibitory influence on the target neuron. Picrotoxin reduces conductance through the channel by reducing not only the opening frequency but also the mean open time. Picrotoxin also antagonizes GABAC receptors (also called GABAA-rho receptors) but the result of this action is not known. The GABAC receptor is also linked to chloride channels, with distinct physiological and pharmacological properties. In contrast to the fast and transient responses elicited from GABAA receptors, GABAC receptors mediate slow and sustained responses.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityOral, mouse: LD50 = 15 mg/kg. In large doses it is a powerful poison, causing unconsciousness, delirium, convulsions, gastro-enteritis and stimulation of the respiratory centre followed by paralysis, from which death sometimes results.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8434
Blood Brain Barrier+0.5
Caco-2 permeable-0.6151
P-glycoprotein substrateSubstrate0.794
P-glycoprotein inhibitor IInhibitor0.7418
P-glycoprotein inhibitor IINon-inhibitor0.9201
Renal organic cation transporterNon-inhibitor0.8832
CYP450 2C9 substrateNon-substrate0.8446
CYP450 2D6 substrateNon-substrate0.866
CYP450 3A4 substrateSubstrate0.6596
CYP450 1A2 substrateNon-inhibitor0.8981
CYP450 2C9 substrateNon-inhibitor0.9071
CYP450 2D6 substrateNon-inhibitor0.9307
CYP450 2C19 substrateNon-inhibitor0.8809
CYP450 3A4 substrateNon-inhibitor0.5167
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.929
Ames testAMES toxic0.6089
CarcinogenicityNon-carcinogens0.9354
BiodegradationNot ready biodegradable1.0
Rat acute toxicity3.2615 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9951
hERG inhibition (predictor II)Non-inhibitor0.9013
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point203.5 °CPhysProp
water solubility4100 mg/LYALKOWSKY,SH & DANNENFELSER,RM (1992)
logP-2.229Not Available
Predicted Properties
PropertyValueSource
logP-1.1ChemAxon
pKa (Strongest Acidic)13.6ChemAxon
pKa (Strongest Basic)-2.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area105.59 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity68.29 m3·mol-1ChemAxon
Polarizability28.53 Å3ChemAxon
Number of Rings10ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraMS
References
Synthesis ReferenceNot Available
General Reference
  1. Link
  2. Ehrenberger K, Benkoe E, Felix D: Suppressive action of picrotoxin, a GABA antagonist, on labyrinthine spontaneous nystagmus and vertigo in man. Acta Otolaryngol. 1982 Mar-Apr;93(3-4):269-73. Pubmed
External Links
ATC CodesNot Available
AHFS Codes
  • 92:02.00*
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (75.2 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Gamma-aminobutyric acid receptor subunit rho-1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit rho-1 P24046 Details

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. Pubmed
  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. Pubmed
  3. Law RJ, Lightstone FC: Gaba receptor insecticide non-competitive antagonists may bind at allosteric modulator sites. Int J Neurosci. 2008 May;118(5):705-34. Pubmed
  4. Richter D, Luhmann HJ, Kilb W: Intrinsic activation of GABA receptors suppresses epileptiform activity in the cerebral cortex of immature mice. Epilepsia. 2010 May 14. Pubmed

2. Gamma-aminobutyric acid receptor subunit alpha-1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit alpha-1 P14867 Details

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. Pubmed
  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. Pubmed
  3. Law RJ, Lightstone FC: Gaba receptor insecticide non-competitive antagonists may bind at allosteric modulator sites. Int J Neurosci. 2008 May;118(5):705-34. Pubmed
  4. Richter D, Luhmann HJ, Kilb W: Intrinsic activation of GABA receptors suppresses epileptiform activity in the cerebral cortex of immature mice. Epilepsia. 2010 May 14. Pubmed
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Glycine receptor subunit alpha-2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Glycine receptor subunit alpha-2 P23416 Details

References:

  1. Yang Z, Cromer BA, Harvey RJ, Parker MW, Lynch JW: A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore. J Neurochem. 2007 Oct;103(2):580-9. Epub 2007 Aug 20. Pubmed
  2. Wang DS, Buckinx R, Lecorronc H, Mangin JM, Rigo JM, Legendre P: Mechanisms for picrotoxinin and picrotin blocks of alpha2 homomeric glycine receptors. J Biol Chem. 2007 Jun 1;282(22):16016-35. Epub 2007 Apr 3. Pubmed

4. Glycine receptor subunit alpha-3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Glycine receptor subunit alpha-3 O75311 Details

References:

  1. Yang Z, Cromer BA, Harvey RJ, Parker MW, Lynch JW: A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore. J Neurochem. 2007 Oct;103(2):580-9. Epub 2007 Aug 20. Pubmed

Enzymes

1. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

References:

  1. Sadar MD, Ash R, Andersson TB: Picrotoxin is a CYP1A1 inducer in rainbow trout hepatocytes. Biochem Biophys Res Commun. 1995 Sep 25;214(3):1060-6. Pubmed
  2. Sadar MD, Westlind A, Blomstrand F, Andersson TB: Induction of CYP1A1 by GABA receptor ligands. Biochem Biophys Res Commun. 1996 Dec 4;229(1):231-7. Pubmed

2. Glutamine synthetase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Glutamine synthetase P15104 Details

References:

  1. Loscher W, Frey HH: Effect of convulsant and anticonvulsant agents on level and metabolism of gamma-aminobutyric acid in mouse brain. Naunyn Schmiedebergs Arch Pharmacol. 1977 Feb;296(3):263-9. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on March 05, 2014 15:57