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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
SaltsNot Available
Brand namesNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number124-87-8
WeightAverage: 602.5832
Monoisotopic: 602.199941174
Chemical FormulaC30H34O13
InChI KeyInChIKey=VJKUPQSHOVKBCO-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[6.4.1.1^{9,12}.0^{3,5}.0^{5,13}]tetradecane-6,11-dione; (1R,5S,8S,13R,14R)-1-hydroxy-13-methyl-14-(prop-1-en-2-yl)-4,7,10-trioxapentacyclo[6.4.1.1^{9,12}.0^{3,5}.0^{5,13}]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
Mass SpecNot Available
Taxonomy
KingdomNot Available
SuperclassNot Available
ClassNot Available
SubclassNot Available
Direct parentNot Available
Alternative parentsNot Available
SubstituentsNot Available
Classification descriptionNot 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
Property Value Probability
Human Intestinal Absorption + 0.8434
Blood Brain Barrier + 0.5
Caco-2 permeable - 0.6151
P-glycoprotein substrate Substrate 0.794
P-glycoprotein inhibitor I Inhibitor 0.7418
P-glycoprotein inhibitor II Non-inhibitor 0.9201
Renal organic cation transporter Non-inhibitor 0.8832
CYP450 2C9 substrate Non-substrate 0.8446
CYP450 2D6 substrate Non-substrate 0.866
CYP450 3A4 substrate Substrate 0.6596
CYP450 1A2 substrate Non-inhibitor 0.8981
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9307
CYP450 2C19 substrate Non-inhibitor 0.8809
CYP450 3A4 substrate Non-inhibitor 0.5167
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.929
Ames test AMES toxic 0.6089
Carcinogenicity Non-carcinogens 0.9354
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 3.2615 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9951
hERG inhibition (predictor II) Non-inhibitor 0.9013
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
LiquidOral
Solution / dropsOral
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 area105.59ChemAxon
rotatable bond count2ChemAxon
refractivity68.29ChemAxon
polarizability28.53ChemAxon
number of rings10ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
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
ResourceLink
PubChem Compound31304
PubChem Substance46506796
ChemSpider29044
Therapeutic Targets DatabaseDAP000676
PharmGKBPA164777007
IUPHAR4051
Guide to Pharmacology4051
WikipediaPicrotoxin
ATC CodesNot Available
AHFS Codes
  • 92:02.00*
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(75.2 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

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

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

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