{"Abbreviation":"","Aliases":["Spheroidine","Tarichatoxin","Tetrodotoxine","Babylonia japonica toxin 1","Tetrodoxin","Tectin","BJT 1","Maculotoxin","Pft-1 toxin","tetrodotoxina"],"CAS":"4368-28-9","ChEBI":"CHEBI:9506","ChEMBL":"CHEMBL507974","ChemicalClasses":["benzamide"],"Chirality":"absolute","Color/Form":"Crystals","Decomposition":"When heated to decomposition it emits toxic fumes of /Nitrogen oxide/.","Dosing Info":[],"Drug Indication":"For the treatment of chronic and breakthrough pain in advanced cancer patients as well as for the treatment of opioid dependence.","DrugClasses":["opioid"],"EINECS":"224-458-8","European Community (EC) Number":"224-458-8","HeavyAtomCount":22,"IUPACName":"(1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.17,11.01,6]tetradec-3-ene-5,9,12,13,14-pentol","InChI":"InChI=1S/C11H17N3O8/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/h2-7,15-20H,1H2,(H3,12,13,14)/t2-,3-,4-,5+,6-,7+,9+,10-,11+/m1/s1","InChIKey":"CFMYXEVWODSLAX-QOZOJKKESA-N","MeSH Pharmacological Classification":"Drugs that block nerve conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. In contact with a nerve trunk, these anesthetics can cause both sensory and motor paralysis in the innervated area. Their action is completely reversible. (From Gilman AG, et. al., Goodman and Gilman\u0026apos;s The Pharmacological Basis of Therapeutics, 8th ed) Nearly all local anesthetics act by reducing the tendency of voltage-dependent sodium channels to activate. (See all compounds classified as Anesthetics, Local.)","Melting Point":"225 °C","MolecularFormula":"C\u003csub\u003e11\u003c/sub\u003eH\u003csub\u003e17\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e8\u003c/sub\u003e","MolecularWeight":"319.27 g/mol","Opticalactivity":"UNSPECIFIED","Physical Description":"Solid; [HSDB] Colorless solid; [NIOSH] White powder; [MSDSonline]","PrevSalts":[],"PubChemId":11174599,"Record 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.","Spheroidine has been reported in Takifugu flavidus, Takifugu rubripes, and other organisms with data available.","Tetrodotoxin is a neurotoxin with potential analgesic activity. Tetrodotoxin binds to the pores of fast voltage-gated fast sodium channels in nerve cell membranes, inhibiting nerve action potentials and blocking nerve transmission. Although found in various species of fish (such as the pufferfish), newts, frogs, flatworms, and crabs, tetrodotoxin, for which there is no known antidote, is actually produced by bacteria such as Vibrio alginolyticus, Pseudoalteromonas tetraodonis, and other vibrio and pseudomonas bacterial species.","An aminoperhydroquinazoline poison found mainly in the liver and ovaries of fishes in the order tetraodontiformes, which are eaten. Tetrodotoxin is a potent neurotoxin that is produced by bacteria (genus Pseudoalteromonas, Pseudomonas, Vibrio) and found in certain species of Tetraodontiformes (puffer fish, porcupine fish, ocean sunfish, triggerfish), from which its name is derived. It acts on the voltage-gated sodium channels of nerve cells. (L1060) 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.\n","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."],"References":[{"Name":"Wikipedia","Urls":[{"Link":"https://en.wikipedia.org/wiki/Tetrodotoxin","Name":"Tetrodotoxin","Sub":false}]},{"Name":"Wikidata","Urls":[{"Link":"https://www.wikidata.org/wiki/Q76416754","Name":"Tetrodotoxin","Sub":false}]},{"Name":"DrugBank","Urls":[{"Link":"https://go.drugbank.com/drugs/DB05232","Name":"Tetrodotoxin","Sub":false}]},{"Name":"PubChem","Urls":[{"Link":"https://pubchem.ncbi.nlm.nih.gov/compound/11174599","Name":"Tetrodotoxin","Sub":false}]},{"Name":"ChemSpider","Urls":[{"Link":"https://www.chemspider.com/Chemical-Structure.21248349.html","Name":"Tetrodotoxin","Sub":false}]},{"Name":"ChEMBL","Urls":[{"Link":"https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL507974","Name":"Tetrodotoxin","Sub":false}]},{"Name":"ChEBI","Urls":[{"Link":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9506","Name":"Tetrodotoxin","Sub":false}]},{"Name":"Common Chemistry","Urls":[{"Link":"https://commonchemistry.cas.org/detail?cas_rn=4368-28-9","Name":"Tetrodotoxin","Sub":false}]},{"Name":"UNII","Urls":[{"Link":"https://gsrs.ncats.nih.gov/ginas/app/ui/substances/3KUM2721U9","Name":"Tetrodotoxin","Sub":false}]},{"Name":"EPA DSSTox","Urls":[{"Link":"https://comptox.epa.gov/dashboard/chemical/details/DTXSID10881342","Name":"Tetrodotoxin","Sub":false}]}],"Reported Fatal Dose":"A fatal dose may be as little as 1 to 4 mg per person.","SMILES":"C([C@@]1([C@H]2[C@@H]3[C@H](N=C(N[C@@]34[C@@H]([C@@H]1O[C@]([C@H]4O)(O2)O)O)N)O)O)O","Solubility":"Soluble in dilute acetic acid; slightly soluble in dry alcohol, ether; practically insoluble in other organic solvents","Stability/Shelf Life":"Stable to boiling except in an alkaline solution.","StoreUNII":["3KUM2721U9"],"StructureBase64":"<svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" height="92.528mm" version="1.2" viewBox="0 0 102.653 92.528" width="102.653mm">
      
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","Therapeutic Uses":"/EXPL THER/ Corneal injury can produce photophobia, an aversive sensitivity to light. Using topical application of lidocaine, a local anesthetic, and tetrodotoxin (TTX), a selective voltage-sensitive sodium channel blocker, we assessed whether enhanced aversiveness to light induced by corneal injury in rats was caused by enhanced activity in corneal afferents. Eye closure induced by 30 seconds of exposure to bright light (460-485 nm) was increased 24 hours after corneal injury induced by de-epithelialization. Although the topical application of lidocaine did not affect the baseline eye closure response to bright light in control rats, it eliminated the enhancement of the response to the light stimulus after corneal injury (photophobia). Similarly, topical application of TTX had no effect on the eye closure response to bright light in rats with intact corneas, but it markedly attenuated photophobia in rats with corneal injury. Given the well-established corneal toxicity of local anesthetics, we suggest TTX as a therapeutic option to treat photophobia and possibly other symptoms that occur in clinical diseases that involve corneal nociceptor sensitization.  PERSPECTIVE: We show that lidocaine and TTX attenuate photophobia induced by corneal injury. Although corneal toxicity limits use of local anesthetics, TTX may be a safer therapeutic option to reduce the symptom of photophobia associated with corneal injury.","Title":"Tetrodotoxin","UNII":"3KUM2721U9","Wikidata":"Q76416754","XLogP":-5.9}