Picrotoxin

Identification

Generic Name
Picrotoxin
DrugBank Accession Number
DB00466
Background

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]

Type
Small Molecule
Groups
Experimental
Structure
Weight
Average: 602.5832
Monoisotopic: 602.199941174
Chemical Formula
C30H34O13
Synonyms
  • cocculin

Pharmacology

Indication

Used internally for relieving respiratory distress. Also for use as an antidote in poisoning by CNS depressants, especially barbiturates.

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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.

TargetActionsOrganism
AGamma-aminobutyric acid receptor subunit rho-1
antagonist
Humans
AGamma-aminobutyric acid receptor subunit alpha-1
antagonist
Humans
UGlycine receptor subunit alpha-2
antagonist
Humans
UGlycine receptor subunit alpha-3
antagonist
Humans
UGlycine receptor subunit alpha-1
antagonist
Humans
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

Adverse Effects
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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.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Furopyrans
Sub Class
Not Available
Direct Parent
Furopyrans
Alternative Parents
Oxepanes / Dicarboxylic acids and derivatives / Gamma butyrolactones / Oxanes / Pyrans / Furans / Tetrahydrofurans / Tertiary alcohols / Carboxylic acid esters / Cyclic alcohols and derivatives
show 6 more
Substituents
Alcohol / Aliphatic heteropolycyclic compound / Caprolactone / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Cyclic alcohol / Dialkyl ether / Dicarboxylic acid or derivatives / Ether
show 15 more
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
ZLT174DL7U
CAS number
124-87-8
InChI Key
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

References

General References
  1. Ehrenberger K, Benkoe E, Felix D: Suppressive action of picrotoxin, a GABA antagonist, on labyrinthine spontaneous nystagmus and vertigo in man. Acta Otolaryngol. 1982;93(1-6):269-73. [Article]
  2. Link [Link]
Human Metabolome Database
HMDB0014609
PubChem Compound
31304
PubChem Substance
46506796
ChemSpider
29044
ChEMBL
CHEMBL1908342
Therapeutic Targets Database
DAP000676
PharmGKB
PA164777007
Guide to Pharmacology
GtP Drug Page
Wikipedia
Picrotoxin
MSDS
Download (75.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)203.5 °CPhysProp
water solubility4100 mg/LYALKOWSKY,SH & DANNENFELSER,RM (1992)
logP-2.229Not Available
Predicted Properties
PropertyValueSource
Water Solubility24.5 mg/mLALOGPS
logP0.09ALOGPS
logP-1.1Chemaxon
logS-1.1ALOGPS
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
Polarizability28.52 Å3Chemaxon
Number of Rings10Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9307
CYP450 2C19 inhibitorNon-inhibitor0.8809
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Mass Spectrum (Electron Ionization)MSsplash10-0a4m-9400000000-4265da630cb3536f0c8d
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-225.05061
predicted
DeepCCS 1.0 (2019)
[M+H]+226.7743
predicted
DeepCCS 1.0 (2019)
[M+Na]+233.07108
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Gaba-a receptor activity
Specific Function
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...
Gene Name
GABRR1
Uniprot ID
P24046
Uniprot Name
Gamma-aminobutyric acid receptor subunit rho-1
Molecular Weight
55882.91 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. [Article]
  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. [Article]
  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. doi: 10.1080/00207450701750216. [Article]
  4. Richter D, Luhmann HJ, Kilb W: Intrinsic activation of GABA(A) receptors suppresses epileptiform activity in the cerebral cortex of immature mice. Epilepsia. 2010 Aug;51(8):1483-92. doi: 10.1111/j.1528-1167.2010.02591.x. Epub 2010 May 14. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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...
Gene Name
GABRA1
Uniprot ID
P14867
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-1
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. [Article]
  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. [Article]
  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. doi: 10.1080/00207450701750216. [Article]
  4. Richter D, Luhmann HJ, Kilb W: Intrinsic activation of GABA(A) receptors suppresses epileptiform activity in the cerebral cortex of immature mice. Epilepsia. 2010 Aug;51(8):1483-92. doi: 10.1111/j.1528-1167.2010.02591.x. Epub 2010 May 14. [Article]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Transmitter-gated ion channel activity
Specific Function
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).
Gene Name
GLRA2
Uniprot ID
P23416
Uniprot Name
Glycine receptor subunit alpha-2
Molecular Weight
52001.585 Da
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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Transmitter-gated ion channel activity
Specific Function
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).
Gene Name
GLRA3
Uniprot ID
O75311
Uniprot Name
Glycine receptor subunit alpha-3
Molecular Weight
53799.775 Da
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Transmitter-gated ion channel activity
Specific Function
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).
Gene Name
GLRA1
Uniprot ID
P23415
Uniprot Name
Glycine receptor subunit alpha-1
Molecular Weight
52623.35 Da
References
  1. Jensen AA, Kristiansen U: Functional characterisation of the human alpha1 glycine receptor in a fluorescence-based membrane potential assay. Biochem Pharmacol. 2004 May 1;67(9):1789-99. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Vitamin d 24-hydroxylase activity
Specific Function
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 un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Manganese ion binding
Specific Function
This enzyme has 2 functions: it catalyzes the production of glutamine and 4-aminobutanoate (gamma-aminobutyric acid, GABA), the latter in a pyridoxal phosphate-independent manner (By similarity). E...
Gene Name
GLUL
Uniprot ID
P15104
Uniprot Name
Glutamine synthetase
Molecular Weight
42064.15 Da
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. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 03, 2024 02:26