Tetrodotoxin

Identification

Name
Tetrodotoxin
Accession Number
DB05232
Type
Small Molecule
Groups
Investigational
Description

An aminoperhydroquinazoline poison found mainly in the liver and ovaries of fishes in the order tetraodontiformes, which are eaten. The toxin causes paresthesia and paralysis through interference with neuromuscular conduction. Tetrodotoxin is being investigated by Wex Pharmaceuticals for the treatment of chronic and breakthrough pain in advanced cancer patients as well as for the treatment of opioid dependence.

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Tectin / Tetrodin
Categories
UNII
3KUM2721U9
CAS number
4368-28-9
Weight
Average: 319.268
Monoisotopic: 319.101564535
Chemical Formula
C11H17N3O8
InChI Key
SLBCPBUVHCASIJ-UFHSVNPDSA-O
InChI
InChI=1S/C11H16N3O8/c12-8-13-6(17)2-4-9(19,1-15)5-3(16)10(2,14-8)7(18)11(20,21-4)22-5/h2-7,15-19H,1H2,(H3,12,13,14)/q-1/p+1/t2?,3?,4?,5-,6?,7-,9?,10?,11?/m0/s1
IUPAC Name
(11S,13S)-3-amino-5,12,13,14-tetrahydroxy-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1⁷,¹¹.0¹,⁶]tetradec-3-en-4-ium-9-olate
SMILES
[H][C@]12OC3([O-])OC(C4C(O)[NH+]=C(N)NC4(C1O)[C@@H]3O)C2(O)CO

Pharmacology

Indication

For the treatment of chronic and breakthrough pain in advanced cancer patients as well as for the treatment of opioid dependence.

Pharmacodynamics
Not Available
Mechanism of action

Tetrodotoxin binds to what is known as site 1 of the fast voltage-gated sodium channel. Site 1 is located at the extracellular pore opening of the ion channel. The binding of any molecules to this site will temporarily disable the function of the ion channel. Saxitoxin and several of the conotoxins also bind the same site.

TargetActionsOrganism
USodium channel protein type 1 subunit alphaNot AvailableHuman
USodium channel protein type 2 subunit alphaNot AvailableHuman
USodium channel protein type 3 subunit alphaNot AvailableHuman
USodium channel protein type 8 subunit alphaNot AvailableHuman
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

Death has occurred within 17 minutes of ingestion.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Tetrodotoxin is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Tetrodotoxin.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Tetrodotoxin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Tetrodotoxin.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Tetrodotoxin is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Tetrodotoxin.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when Tetrodotoxin is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Tetrodotoxin.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Tetrodotoxin.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Tetrodotoxin.
Food Interactions
Not Available

References

General References
Not Available
External Links
KEGG Compound
C11692
PubChem Compound
21733122
PubChem Substance
175426959
ChemSpider
27289077
ChEBI
9506
Wikipedia
Tetrodotoxin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedScreeningHealthy Volunteers1
2TerminatedTreatmentPain NOS / Pain, Neuropathic / Peripheral Neuropathy1
3CompletedTreatmentMalignancies / Pain NOS2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
pKa8.76MERCK INDEX (1996)
Predicted Properties
PropertyValueSource
Water Solubility117.0 mg/mLALOGPS
logP0.42ALOGPS
logP-4.8ChemAxon
logS-0.5ALOGPS
pKa (Strongest Acidic)10.4ChemAxon
pKa (Strongest Basic)9.62ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count8ChemAxon
Polar Surface Area194.69 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity86.74 m3·mol-1ChemAxon
Polarizability27.83 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9781
Blood Brain Barrier-0.6809
Caco-2 permeable-0.6763
P-glycoprotein substrateSubstrate0.5082
P-glycoprotein inhibitor INon-inhibitor0.9376
P-glycoprotein inhibitor IINon-inhibitor0.988
Renal organic cation transporterNon-inhibitor0.9066
CYP450 2C9 substrateNon-substrate0.7925
CYP450 2D6 substrateNon-substrate0.7989
CYP450 3A4 substrateNon-substrate0.5602
CYP450 1A2 substrateNon-inhibitor0.8008
CYP450 2C9 inhibitorNon-inhibitor0.884
CYP450 2D6 inhibitorNon-inhibitor0.908
CYP450 2C19 inhibitorNon-inhibitor0.8374
CYP450 3A4 inhibitorNon-inhibitor0.9834
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9821
Ames testNon AMES toxic0.5547
CarcinogenicityNon-carcinogens0.9196
BiodegradationNot ready biodegradable0.9587
Rat acute toxicity2.5238 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9949
hERG inhibition (predictor II)Non-inhibitor0.8694
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
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as tetrodotoxins. These are compounds structurally characterized by the presence of the tetrodotoxin skeleton, which is based on 5,7-(epoxymethanooxy)quinazolin-10-olate moiety.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Tetrodotoxins
Alternative Parents
1,3-dioxanes / Hydropyrimidines / Monosaccharides / Oxanes / Tertiary alcohols / Secondary alcohols / Cyclic alcohols and derivatives / Guanidines / Orthocarboxylic acid derivatives / Propargyl-type 1,3-dipolar organic compounds
show 11 more
Substituents
Tetrodotoxin-skeleton / Meta-dioxane / Hydropyrimidine / 1,4,5,6-tetrahydropyrimidine / Monosaccharide / Oxane / Cyclic alcohol / Tertiary alcohol / Guanidine / Orthocarboxylic acid derivative
show 20 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Alkaloids, Tetrodotoxins (C11692)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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...
Gene Name
SCN1A
Uniprot ID
P35498
Uniprot Name
Sodium channel protein type 1 subunit alpha
Molecular Weight
228969.49 Da
References
  1. Sage D, Salin P, Alcaraz G, Castets F, Giraud P, Crest M, Mazet B, Clerc N: Na(v)1.7 and Na(v)1.3 are the only tetrodotoxin-sensitive sodium channels expressed by the adult guinea pig enteric nervous system. J Comp Neurol. 2007 Oct 1;504(4):363-78. [PubMed:17663442]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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...
Gene Name
SCN2A
Uniprot ID
Q99250
Uniprot Name
Sodium channel protein type 2 subunit alpha
Molecular Weight
227972.64 Da
References
  1. Sage D, Salin P, Alcaraz G, Castets F, Giraud P, Crest M, Mazet B, Clerc N: Na(v)1.7 and Na(v)1.3 are the only tetrodotoxin-sensitive sodium channels expressed by the adult guinea pig enteric nervous system. J Comp Neurol. 2007 Oct 1;504(4):363-78. [PubMed:17663442]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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...
Gene Name
SCN3A
Uniprot ID
Q9NY46
Uniprot Name
Sodium channel protein type 3 subunit alpha
Molecular Weight
226291.905 Da
References
  1. Sage D, Salin P, Alcaraz G, Castets F, Giraud P, Crest M, Mazet B, Clerc N: Na(v)1.7 and Na(v)1.3 are the only tetrodotoxin-sensitive sodium channels expressed by the adult guinea pig enteric nervous system. J Comp Neurol. 2007 Oct 1;504(4):363-78. [PubMed:17663442]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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...
Gene Name
SCN8A
Uniprot ID
Q9UQD0
Uniprot Name
Sodium channel protein type 8 subunit alpha
Molecular Weight
225278.005 Da
References
  1. Sage D, Salin P, Alcaraz G, Castets F, Giraud P, Crest M, Mazet B, Clerc N: Na(v)1.7 and Na(v)1.3 are the only tetrodotoxin-sensitive sodium channels expressed by the adult guinea pig enteric nervous system. J Comp Neurol. 2007 Oct 1;504(4):363-78. [PubMed:17663442]

Drug created on October 21, 2007 16:24 / Updated on November 02, 2018 06:09