View source for Picrotoxin

{{Short description|Chemical compound}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 464206410
|imageL = Picrotoxinin.svg
| imageR = Picrotin.svg
| captionLR = Picrotoxinin (left) and picrotin (right)

<!--Clinical data-->
| tradename =

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 124-87-8
| ATC_prefix = none
| PubChem = 5360688
| IUPHAR_ligand = 4051
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
 | DrugBank = DB00466
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 16736444
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = ZLT174DL7U
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = C09529
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 134126
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 506977

<!--Chemical data-->
| molecular_weight = 
| smiles = CC(=C)[C@H]1[C@@H]2C(=O)O[C@H]1[C@H]3OC(=O)[C@@]54O[C@@H]5C[C@]2(O)[C@@]34C.CC(C)(O)[C@H]5[C@@H]1C(=O)O[C@H]5[C@H]2OC(=O)[C@@]43O[C@@H]4C[C@]1(O)[C@@]23C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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+/m11/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = VJKUPQSHOVKBCO-AHMKVGDJSA-N
}}

'''Picrotoxin''', also known as '''cocculin''', is a poisonous crystalline plant compound. It was first isolated by the French pharmacist and chemist Pierre François Guillaume Boullay (1777–1869) in 1812.<ref>{{cite journal | vauthors = Boullay PF | date = 1812 | title = Analyse chimique de la Coque du Levant, Menispermum cocculus | journal = Bulletin de Pharmacie | language = French | volume = 4 | pages = 5–34 | quote = Menispermum cocculus" has been renamed "Anamirta cocculus" }}</ref> The name "picrotoxin" is a combination of the Greek words "picros" (bitter) and "toxicon" (poison).<ref>(Boullay, 1812), p. 31.</ref> A mixture of two different compounds, picrotoxin occurs naturally in the fruit of the ''[[Anamirta cocculus]]'' plant, although it can also be synthesized chemically.

Due to its interactions with the inhibitory neurotransmitter [[GABA]], picrotoxin acts as a stimulant and convulsant. It mainly impacts the central nervous system, causing seizures and respiratory paralysis in high enough doses.

==Chemical structure and synthesis==

Picrotoxin is an equi[[Mole (unit)|molar]] mixture of two compounds, picrotoxinin (C<sub>15</sub>H<sub>16</sub>O<sub>6</sub>; CAS# 17617-45-7) and picrotin (C<sub>15</sub>H<sub>18</sub>O<sub>7</sub>; CAS# 21416-53-5).<ref>{{cite web | vauthors = Law V, Knox C, Djoumbou Y, Jewison T, Guo AC, Liu Y, Maciejewski A, Arndt D, Wilson M, Neveu V, Tang A | display-authors = 6 |title=Picrotoxin|url=https://www.drugbank.ca/drugs/DB00466|website=DrugBank|access-date=April 26, 2017}}</ref>  Of the two compounds, picrotin is less active.<ref>{{cite journal| vauthors = Gammill R, Tulinsky J  |title=The Chemistry and Pharmacology of GABA<sub>A</sub> and GABA<sub>B</sub> Ligands|journal=Current Medicinal Chemistry|date=1994|volume=1|issue=3|page=242|url=https://books.google.com/books?id=RUIC6BGv2GwC&q=current+medicinal+chemistry+picrotoxin&pg=PA242|access-date=April 26, 2017}}</ref>

Picrotoxin occurs naturally in the fruit of the ''Anamirta cocculus'', a climbing plant from India and other parts of Southeast Asia. The plant is known for its large stems of white wood and sweetly-scented flowers. It produces small stone fruits, ''Cocculus indicus'', which are typically dried.{{citation needed|date=October 2017}}

Currently, there are as many as five total syntheses of picrotoxinin&nbsp;— one of which was published as recently as June 2020.<ref name=Scripps>{{cite journal | vauthors = Crossley SW, Tong G, Lambrecht MJ, Burdge HE, Shenvi RA | title = Synthesis of (-)-Picrotoxinin by Late-Stage Strong Bond Activation | journal = Journal of the American Chemical Society | volume = 142 | issue = 26 | pages = 11376–11381 | date = July 2020 | pmid = 32573211 | doi = 10.1021/jacs.0c05042 | pmc = 8011636 }}</ref> Most syntheses use [[carvone]] as a stereochemical template. 

[[File:Picrotoxinin Synthesis.png|thumb|left|500px|alt=Begin with methyl (1''S'',4''S'',5''R'',7''R'',8''S'',9''R'',10''R'',11''R'')-10-(acetyloxy)-7-hydroxy-11-methyl-3-oxo-9-(prop-1-en-2-yl)-4,5-bis[(trimethylsilyl)oxy]-2-oxatricyclo[5.3.1.0<sup>4</sup>,<sup>11</sup>]undecane-8-carboxylate.  (1) Intramolecular transesterification, releasing methyl acetate; then (2) deprotection of a trimethylsilyl-protected vicinal diol, followed by (3) reductive dehydration to an olefin, and (4) stereospecific epoxidation to a glycidic ester|The final few steps of the Tohoku picrotoxinin synthesis from carvone.<ref>{{cite journal | vauthors =  Trost B, Krische MJ |author-link1=Barry Trost |author-link2=Michael J. Krische|title=Picrotoxinin |journal=Journal of the American Chemical Society |date=1996 |volume=118 |page=233 |url= https://www.chem.wisc.edu/areas/reich/syntheses/picrotoxinin-trost.htm |access-date=May 7, 2017 |doi=10.1021/ja953060r|url-access=subscription }}</ref>]]
In 1988, researchers from Tohoku University in Japan completed a total stereoselective synthesis of both ({{nbh}}){{nbh}}picro&shy;toxinin and {{nowrap|(-)-picrotin}} beginning with (+){{nbh}}5β{{nbh}}hydroxy&shy;[[carvone]]. In this synthesis, eight asymmetric centers were stereo&shy;selectively prepared on a ''cis''-fused hydrindane ring system using several different reactions: a Claisen rearrangement to introduce the quaternary center, an organo&shy;selenium-mediated reduction of an epoxy ketone, and a stereo&shy;specific construction of a glycidic ester.<ref>{{cite journal| vauthors = Miyashita M, Suzuki T, Yoshikoshi A |title=Stereoselective total synthesis of (-)-picrotoxinin and (-)-picrotin|journal=Journal of the American Chemical Society|date=May 1989|volume=111|issue=10|pages=3728–3734|doi=10.1021/ja00192a035|bibcode=1989JAChS.111.3728M }}</ref> 

The June 2020 synthesis instead employed the quick formation of the polycyclic core, followed by the manipulation of oxidation states of key carbon atoms in order to produce the target molecule.<ref name=Scripps /> 

Some research suggests that picritoxin can be made by the cyclofunctionalization of cycloalkenyl systems. Under kinetically controlled conditions, this process generally results in ''exo'' cyclization and forms bridged ring systems like those found in picrotoxin.<ref>{{cite book| vauthors = Trost B, Fleming I  |title=Comprehensive Organic Synthesis|date=1991|publisher=Pergamon Press|location=Oxford, UK|page=373|edition=Volume 4|url=https://books.google.com/books?id=bGl6wAgLcSQC&q=Comprehensive+Organic+Synthesis:+Additions+to+and+Substitutions+as+C-C%5Bpi%5D+bonds&pg=PR4|access-date=May 7, 2017|isbn=9780080405957}}</ref> 

Several techniques have been developed to isolate picrotoxinin and picrotin individually. Reaction with the nearby ''cis'' alcohol is the key obstruction, and can be inhibited by pretreatment ([[protecting group|protection]]) with [[trifluoroacetic anhydride]] in [[pyridine]]:<ref>{{cite journal| vauthors = Corey EJ, Pearce HL |title=Total Synthesis of Picrotin|journal=Tetrahedron Letters|date=1980|volume=21|issue=19|pages=1823–1824|doi=10.1016/s0040-4039(00)92789-8}}</ref>  
[[File:Picrotin_Synthesis.png|frameless|center|500px|alt=Picrotin from picrotoxinin: (1) Protection with trifluoroacetic anhydride, followed by (2) addition of chloromercury trifluoroacetate, which (3) spontaneously decomposes to the alcohol and can then be (4) deprotected]]
Picrotoxin has also been used as a starting material in several synthetic processes, including the creation of ''dl''-picrotoxadiene, which retains certain features of the picrotoxin skeleton.<ref>{{cite journal| vauthors = Conroy H |title=Picrotoxin. II. The Skeleton of Picrotoxinin. The Total Synthesis of dl-Picrotoxadiene|journal=Journal of the American Chemical Society|date=June 1952|volume=74|issue=12|pages=3046–3051|doi=10.1021/ja01132a028|bibcode=1952JAChS..74.3046C }}</ref>

==Mechanism of action==

Some crustacean muscle fibers have excitatory and inhibitory innervation.  Picrotoxin blocks inhibition.<ref>{{cite journal | vauthors = Van Der Kloot WG, Robbins J, Cooke IM | title = Blocking by picrotoxin of peripheral inhibition in crayfish | journal = Science | volume = 127 | issue = 3297 | pages = 521–522 | date = March 1958 | doi = 10.1126/science.127.3297.521 | pmid = 13529017 | bibcode = 1958Sci...127..521V }}</ref> Two different but related theories have been proposed for the mechanism by which picrotoxin acts on [[synapses]]. One theory is that it acts as a [[Channel blocker|non-competitive channel blocker]] for [[GABAA receptor|GABA<sub>A</sub> receptor]] chloride channels,<ref>{{cite journal | vauthors = Rho JM, Donevan SD, Rogawski MA | title = Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons | journal = The Journal of Physiology | volume = 497 | issue = 2 | pages = 509–22 | date = December 1996 | pmid = 8961191 | pmc = 1161000 | doi = 10.1113/jphysiol.1996.sp021784 }}</ref> specifically the gamma-aminobutyric acid-activated chloride ionophore.<ref>{{cite web| vauthors = Law V, Knox C, Djoumbou Y, Jewison T, Guo AC, Liu Y, Maciejewski A, Arndt D, Wilson M, Neveu V, Tang A | display-authors = 6|title= Picrotoxin|url= https://www.drugbank.ca/drugs/DB00466|website=DrugBank|access-date=April 26, 2017}}</ref> A 2006 study found that, while not structurally similar to GABA, picrotoxin prevents ion flow through the chloride channels activated by GABA. It likely acts within the ion channels themselves, rather than at GABA recognition sites. Because it inhibits channels activated by GABA, GABA-enhancing drugs like barbiturates and benzodiazepines can be used as an antidote.<ref>{{cite journal | vauthors = Olsen RW | title = Picrotoxin-like channel blockers of GABAA receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 16 | pages = 6081–2 | date = April 2006 | pmid = 16606858 | pmc = 1458832 | doi = 10.1073/pnas.0601121103 | bibcode = 2006PNAS..103.6081O | doi-access = free }}</ref>

Other research suggests that the toxin acts instead as a [[non-competitive antagonist]], or inhibitor, for GABA receptors. A study by Newland and Cull-Candy found that, in high enough concentrations, picrotoxin reduced the amplitude of GABA currents. Their data indicated that it was unlikely that picrotoxin acted simply as a voltage-gated channel blocker, although it did reduce the frequency of channel openings. Rather, they found that picrotoxin “binds preferentially to an agonist bound form of the receptor.” This means that, even in the presence of low concentrations of picrotoxin, the response of neurons to GABA is reduced.<ref>{{cite journal | vauthors = Newland CF, Cull-Candy SG | title = On the mechanism of action of picrotoxin on GABA receptor channels in dissociated sympathetic neurones of the rat | journal = The Journal of Physiology | volume = 447 | pages = 191–213 | date = February 1992 | pmid = 1317428 | pmc = 1176032 | doi = 10.1113/jphysiol.1992.sp018998 }}</ref>

==Toxicity==

Picrotoxin acts as a central nervous system and respiratory stimulant. It is extremely toxic to fish and humans, as well as rodents and other mammals. According to the Register of Toxic Effects of Chemical Substances, the LDLo, or lowest reported lethal dose, is 0.357&nbsp;mg/kg. Symptoms of picrotoxin poisoning include coughing, difficulty breathing, headache, dizziness, confusion, gastro-intestinal distress, nausea or vomiting, and changes in heart rate and blood pressure. Although especially dangerous if swallowed, systemic effects can also result from inhalation or absorption into the blood stream through lesions in the skin.<ref>{{cite web|title=Picrotoxin|url=http://datasheets.scbt.com/sc-202765.pdf|publisher=Santa Cruz Biotechnology|access-date=April 26, 2017}}</ref>  Picrotoxin also acts as a convulsant.  In larger doses, it has been found to induce clonic seizures or cardiac dysrhythmias, with especially high doses ultimately proving fatal, typically due to respiratory paralysis.<ref>{{cite web|title=Picrotoxin|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+6385|website=Toxnet|publisher=U.S. National Laboratory of Medicine|access-date=April 26, 2017}}</ref>

==Clinical applications and other uses==

Due to its toxicity, picrotoxin is now most commonly used as a research tool. However, due to its antagonist effect on GABA receptors, it has been used as a central nervous system stimulant. It was also previously used as an antidote for poisoning by CNS depressants, especially [[barbiturate]]s.<ref>{{cite journal | vauthors = Nilsson E, Eyrich B | title = On treatment of barbiturate poisoning | journal = Acta Medica Scandinavica | volume = 137 | issue = 6 | pages = 381–9 | year = 2009 | pmid = 15432128 | doi = 10.1111/j.0954-6820.1950.tb12129.x }}</ref>

Although not commonly used, picrotoxin is effective as both a pesticide and a [[pediculicide]]. In the 19th century, it was used in the preparation of '''hard multum''', which was added to beer to make it more intoxicating. This preparation has since been outlawed.<ref>{{cite book | vauthors = Böttger A, Vothknecht U, Bolle C, Wolf A | title=Lessons on Caffeine, Cannabis & Co: Plant-derived Drugs and their Interaction with Human Receptors | date=2018 | page=129 | doi=10.1007/978-3-319-99546-5_8 | chapter=Plant-Derived Drugs Affecting Ion Channels | series=Learning Materials in Biosciences | isbn=978-3-319-99545-8 }}</ref><ref>{{cite book | vauthors = Bell J |date=1869 |title=Report of the Committee on the Relations of Alcohol to Medicine |publisher=Collins |location=United States |page=32}}</ref>

Despite its potential toxicity to mammals in large enough doses, picrotoxin is also sometimes used as a performance enhancer in horses. It is classified as an illegal "Class I substance" by the [[American Quarter Horse Association]]. Substances that are classified as “Class I” are likely to affect performance and have no therapeutic use in equine medicine.<ref>{{cite web|title=Uniform Classification Guidelines for Foreign Substances and Recommended Penalties and Model Rule|url=https://www.in.gov/hrc/files/Drug_Classification_Guidelines_and_Penalties.pdf|publisher=Association of Racing Commissioners International, Inc.|access-date=April 26, 2017}}</ref> In 2010, quarter horse trainer Robert Dimitt was suspended after his horse, Stoli Signature, tested positive for the substance. As with humans, it is used to counteract barbiturate poisoning.<ref>{{cite news| vauthors = Lemoreaux P |title=Two Quarter Horse trainers suspended for drug violations at Prairie Meadows|url=http://www.drf.com/news/two-quarter-horse-trainers-suspended-drug-violations-prairie-meadows|access-date=April 26, 2017|agency=Daily Racing Form|publisher=Daily Racing Form|date=September 2, 2017}}</ref>

== See also ==
* [[GABAA receptor negative allosteric modulator|GABA<sub>A</sub> receptor negative allosteric modulator]]
* [[GABAA receptor#Ligands|GABA<sub>A</sub> receptor § Ligands]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Ehrenberger K, Benkoe E, Felix D | title = Suppressive action of picrotoxin, a GABA antagonist, on labyrinthine spontaneous nystagmus and vertigo in man | journal = Acta Oto-Laryngologica | volume = 93 | issue = 1–6 | pages = 269–73 | year = 1982 | pmid = 7064710 | doi = 10.3109/00016488209130882 }}
* {{ cite journal | vauthors = Dupont L, Dideberg O, Lamotte-Brasseur J, Angenot L | title = Structure cristalline et moléculaire de la picrotoxine, C<sub>15</sub>H<sub>16</sub>O<sub>6</sub>·C<sub>15</sub>H<sub>18</sub>O<sub>7</sub> | language = French | journal = Acta Crystallographica B | year = 1976 | volume = 32 | issue = 11 | pages = 2987–2993 | doi = 10.1107/S0567740876009424 | hdl = 2268/31560 | doi-access =  | bibcode = 1976AcCrB..32.2987D | hdl-access = free }}
*{{ cite book | title = Basic Neurochemistry: Molecular, Cellular and Medical Aspects | journal = <!-- Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th Edition -->| edition = 6th | vauthors = Olsen RW, DeLorey TM | veditors = Siegel GJ, Agranoff BW, Albers RW | location = Philadelphia, PA, USA | publisher = Lippincott-Raven | year = 1999 | chapter-url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181 | chapter = GABA Receptor Physiology and Pharmacology |display-editors=etal}}
{{refend}}

{{Neurotoxins}}
{{GABAergics}}
{{Glycinergics}}
{{Convulsants}}

[[Category:GABAA receptor negative allosteric modulators]]
[[Category:GABAA-rho receptor negative allosteric modulators]]
[[Category:Glycine receptor antagonists]]
[[Category:Convulsants]]
[[Category:Lactones]]
[[Category:Epoxides]]
[[Category:Chloride channel blockers]]
[[Category:Neurotoxins]]
[[Category:Plant toxins]]