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targets (4) enzymes (2)
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Identification
Name Picrotoxin
Accession Number DB00466 (APRD00269)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Cocculin
Cocculus
Coques du levant
Fish berry
Indian berry
Oriental berry
Brand mixtures Not Available
Categories
  • Central Nervous System Stimulants
  • Stimulants
  • Anti-barbituates
  • GABA receptor antagonists
  • Antidotes
  • Convulsants
  • GABA Antagonists
CAS number 124-87-8
Weight Average: 602.5832
Monoisotopic: 602.199941174
Chemical Formula C30H34O13
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Lactones
Substructures
  • Carboxylic Acids and Derivatives
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Pyrans
  • Acetates
  • Lactones
  • Ethers
  • Alcohols and Polyols
  • Heterocyclic compounds
  • Furans
  • Epoxides
Pharmacology
Indication Used internally for relieving respiratory distress. Also for use as an antidote in poisoning by CNS depressants, especially barbiturates.
Pharmacodynamics Picrotoxin 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 action Picrotoxin 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.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism
Not Available
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity Oral, 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
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms
Form Route Strength
Liquid Oral
Solution / drops Oral
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 203.5 °C PhysProp
water solubility 4100 mg/L YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP -2.229 Not Available
Predicted Properties
Property Value Source
logP -1.1 ChemAxon
pKa (strongest acidic) 13.6 ChemAxon
pKa (strongest basic) -2.8 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 105.59 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 68.29 ChemAxon
polarizability 28.53 ChemAxon
References
Synthesis Reference Not 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
Resource Link
PubChem Compound 31304 Link_out
PubChem Substance 46506796 Link_out
ChemSpider 29044 Link_out
Therapeutic Targets Database DAP000676 Link_out
PharmGKB PA164777007 Link_out
IUPHAR 4051 Link_out
Guide to Pharmacology 4051 Link_out
Wikipedia http://en.wikipedia.org/wiki/Picrotoxin Link_out
ATC Codes Not Available
AHFS Codes
  • 92:02.00*
PDB Entries Not Available
FDA label Not Available
MSDS show (75.2 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Gamma-aminobutyric-acid receptor subunit rho-1

Pharmacological action: yes
Actions: antagonist

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. Rho-1 GABA receptor could play a role in retinal neurotransmission

Organism class: human
UniProt ID: P24046 Link_out
Gene: GABRR1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: antagonist

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel

Organism class: human
UniProt ID: P14867 Link_out
Gene: GABRA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: antagonist

The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing)

Organism class: human
UniProt ID: P23416 Link_out
Gene: GLRA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: antagonist

The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing)

Organism class: human
UniProt ID: O75311 Link_out
Gene: GLRA3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P04798 Link_out
Gene: CYP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

ATP + L-glutamate + NH(3) = ADP + phosphate + L-glutamine

UniProt ID: P15104 Link_out
Gene: GLUL Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:19