Jump to content

Picrotoxin: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
m link carvone using Find link
Line 50: Line 50:
Currently, not much information exists regarding the lab synthesis of picrotoxin. Some research suggests that it 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|last1=Trost|first1=Barry|last2=Fleming|first2=Ian|title=Comprehensive Organic Synthesis|date=1991|publisher=Pergamon Press|location=Oxford, UK|page=373|edition=Volume 4|url=https://books.google.com/?id=bGl6wAgLcSQC&pg=PR4&lpg=PR4&dq=Comprehensive+Organic+Synthesis:+Additions+to+and+Substitutions+as+C-C%5Bpi%5D+bonds#v=onepage&q=Comprehensive%20Organic%20Synthesis%3A%20Additions%20to%20and%20Substitutions%20as%20C-C%5Bpi%5D%20bonds&f=false|accessdate=May 7, 2017|isbn=9780080405957}}</ref> Additionally, several syntheses have been proposed for picrotoxinin and picrotin, the two molecules that make up picrotoxin. In 1980, a process to convert picrotoxinin to picrotin was discovered. This synthesis beings by treating picrotoxin with trifluoroacetic anhydride in pyridine to separate the components.<ref>{{cite journal|last1=Corey|first1=E|last2=Pearce|first2=Homer|title=Total Synthesis of Picrotin|journal=Tetrahedron Letters|date=1980|volume=21|issue=19|pages=1823–1824|url=http://ac.els-cdn.com/S0040403900927898/1-s2.0-S0040403900927898-main.pdf?_tid=4ba02e8e-334a-11e7-9499-00000aab0f26&acdnat=1494178164_ac007ffba87a28f941df95cb09ced52c|accessdate=May 7, 2017|doi=10.1016/s0040-4039(00)92789-8}}</ref>
Currently, not much information exists regarding the lab synthesis of picrotoxin. Some research suggests that it 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|last1=Trost|first1=Barry|last2=Fleming|first2=Ian|title=Comprehensive Organic Synthesis|date=1991|publisher=Pergamon Press|location=Oxford, UK|page=373|edition=Volume 4|url=https://books.google.com/?id=bGl6wAgLcSQC&pg=PR4&lpg=PR4&dq=Comprehensive+Organic+Synthesis:+Additions+to+and+Substitutions+as+C-C%5Bpi%5D+bonds#v=onepage&q=Comprehensive%20Organic%20Synthesis%3A%20Additions%20to%20and%20Substitutions%20as%20C-C%5Bpi%5D%20bonds&f=false|accessdate=May 7, 2017|isbn=9780080405957}}</ref> Additionally, several syntheses have been proposed for picrotoxinin and picrotin, the two molecules that make up picrotoxin. In 1980, a process to convert picrotoxinin to picrotin was discovered. This synthesis beings by treating picrotoxin with trifluoroacetic anhydride in pyridine to separate the components.<ref>{{cite journal|last1=Corey|first1=E|last2=Pearce|first2=Homer|title=Total Synthesis of Picrotin|journal=Tetrahedron Letters|date=1980|volume=21|issue=19|pages=1823–1824|url=http://ac.els-cdn.com/S0040403900927898/1-s2.0-S0040403900927898-main.pdf?_tid=4ba02e8e-334a-11e7-9499-00000aab0f26&acdnat=1494178164_ac007ffba87a28f941df95cb09ced52c|accessdate=May 7, 2017|doi=10.1016/s0040-4039(00)92789-8}}</ref>


In 1988, researchers from Tohoku University in Japan completed a total stereoselective synthesis of both (-)-picrotoxinin and (-)-picrotin beginning with (+)-5β-hydroxycarvone. In this synthesis, eight asymmetric centers were stereoselectively prepared on a cis-fused hydrindane ring system using several different reactions: a Claisen rearrangement to introduce the quaternary center, an organoselenium-mediated reduction of an epoxy ketone, and a stereospecific construction of a glycidic ester.<ref>{{cite journal|last1=Miyashita Akira|first1=Masaaki|last2=Suzuki|first2=Toshio|last3=Yoshikoshi|first3=Akira|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}}</ref> The last steps of this process are shown below.<ref>{{cite journal|authorlink1=Barry Trost|authorlink2=Michael J. Krische|last1=Trost|first1=Barry|last2=Krische|first2=M|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|accessdate=May 7, 2017|doi=10.1021/ja953060r}}</ref>
In 1988, researchers from Tohoku University in Japan completed a total stereoselective synthesis of both (-)-picrotoxinin and (-)-picrotin beginning with (+)-5β-hydroxy[[carvone]]. In this synthesis, eight asymmetric centers were stereoselectively prepared on a cis-fused hydrindane ring system using several different reactions: a Claisen rearrangement to introduce the quaternary center, an organoselenium-mediated reduction of an epoxy ketone, and a stereospecific construction of a glycidic ester.<ref>{{cite journal|last1=Miyashita Akira|first1=Masaaki|last2=Suzuki|first2=Toshio|last3=Yoshikoshi|first3=Akira|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}}</ref> The last steps of this process are shown below.<ref>{{cite journal|authorlink1=Barry Trost|authorlink2=Michael J. Krische|last1=Trost|first1=Barry|last2=Krische|first2=M|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|accessdate=May 7, 2017|doi=10.1021/ja953060r}}</ref>


[[File:Picrotin_Synthesis.png|thumb|center|500px|alt=The synthesis of picrotin from picrotoxinin|Picrotin can be synthesized from picrotoxinin.]]
[[File:Picrotin_Synthesis.png|thumb|center|500px|alt=The synthesis of picrotin from picrotoxinin|Picrotin can be synthesized from picrotoxinin.]]

Revision as of 17:48, 10 December 2018

Picrotoxin
Picrotoxinin (left) and picrotin (right)
Clinical data
ATC code
  • none
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.288 Edit this at Wikidata
Chemical and physical data
3D model (JSmol)
  • 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
  • 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+/m11/s1 checkY
  • Key:VJKUPQSHOVKBCO-AHMKVGDJSA-N checkY
 ☒NcheckY (what is this?)  (verify)

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.[1] The name "picrotoxin" is a combination of the Greek words "picros" (bitter) and "toxicon" (poison).[2] 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 equimolar mixture of two compounds, picrotoxinin (C15H16O6; CAS# 17617-45-7) and picrotin (C15H18O7; CAS# 21416-53-5).[3] Of the two compounds, picrotin is less active.[4]

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]

Currently, not much information exists regarding the lab synthesis of picrotoxin. Some research suggests that it 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.[5] Additionally, several syntheses have been proposed for picrotoxinin and picrotin, the two molecules that make up picrotoxin. In 1980, a process to convert picrotoxinin to picrotin was discovered. This synthesis beings by treating picrotoxin with trifluoroacetic anhydride in pyridine to separate the components.[6]

In 1988, researchers from Tohoku University in Japan completed a total stereoselective synthesis of both (-)-picrotoxinin and (-)-picrotin beginning with (+)-5β-hydroxycarvone. In this synthesis, eight asymmetric centers were stereoselectively prepared on a cis-fused hydrindane ring system using several different reactions: a Claisen rearrangement to introduce the quaternary center, an organoselenium-mediated reduction of an epoxy ketone, and a stereospecific construction of a glycidic ester.[7] The last steps of this process are shown below.[8]

The synthesis of picrotin from picrotoxinin
Picrotin can be synthesized from picrotoxinin.
The synthesis of picrotoxinin from carvone
The final few steps of the synthesis of picrotoxinin from carvone.

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.[9]

Mechanism of action

Some crustacean muscle fibers have excitatory and inhibitory innervation. Picrotoxin blocks inhibition. [10] 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 non-competitive channel blocker for GABAA receptor chloride channels,[11] specifically the gamma-aminobutyric acid-activated chloride ionophore.[12] 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.[13]

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.[14]

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 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.[15] 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.[16]

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 barbiturates.[17]

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.[citation needed]

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.[18] 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.[19]

See also

References

  1. ^ Boullay, P. F. G. (1812). "Analyse chimique de la Coque du Levant, Menispermum cocculus". Bulletin de Pharmacie (in French). 4: 5–34. (Note: "Menispermum cocculus" has been renamed "Anamirta cocculus".)
  2. ^ (Boullay, 1812), p. 31.
  3. ^ Law, V; Knox, C; Djoumbou, Y; Jewison, T; Guo, AC; Liu, Y; Maciejewski, A; Arndt, D; Wilson, M; Neveu, V; Tang, A; Gabriel, G; Ly, C; Adamjee, S; Dame, ZT; Han, B; Zhou, Y; Wishart, DS. "Picrotoxin". DrugBank. DrugBank. Retrieved April 26, 2017.
  4. ^ Gammill, Ronald; Tulinsky, John (1994). "The Chemistry and Pharmacology of GABAA and GABAB Ligands". Current Medicinal Chemistry. 1 (3): 242. Retrieved April 26, 2017.
  5. ^ Trost, Barry; Fleming, Ian (1991). Comprehensive Organic Synthesis (Volume 4 ed.). Oxford, UK: Pergamon Press. p. 373. ISBN 9780080405957. Retrieved May 7, 2017.
  6. ^ Corey, E; Pearce, Homer (1980). "Total Synthesis of Picrotin" (PDF). Tetrahedron Letters. 21 (19): 1823–1824. doi:10.1016/s0040-4039(00)92789-8. Retrieved May 7, 2017.
  7. ^ Miyashita Akira, Masaaki; Suzuki, Toshio; Yoshikoshi, Akira (May 1989). "Stereoselective total synthesis of (-)-picrotoxinin and (-)-picrotin". Journal of the American Chemical Society. 111 (10): 3728–3734. doi:10.1021/ja00192a035.
  8. ^ Trost, Barry; Krische, M (1996). "Picrotoxinin". Journal of the American Chemical Society. 118: 233. doi:10.1021/ja953060r. Retrieved May 7, 2017.
  9. ^ Conroy, Harold (June 1952). "Picrotoxin. II. The Skeleton of Picrotoxinin. The Total Synthesis of dl-Picrotoxadiene". Journal of the American Chemical Society. 74 (12): 3046–3051. doi:10.1021/ja01132a028.
  10. ^ W. G. Van der Kloot; J. Robbins; I. Cooke (1958). "Blocking by picrotoxin of peripheral inhibition in crayfish". Science. 127: 52l–522.
  11. ^ Rho, J M; Donevan, S D; Rogawski, M A (December 1, 1996). "Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons". The Journal of Physiology. 497 (2): 509–522. doi:10.1113/jphysiol.1996.sp021784. PMC 1161000. PMID 8961191.
  12. ^ Law, V; Knox, C; Djoumbou, Y; Jewison, T; Guo, AC; Liu, Y; Maciejewski, A; Arndt, D; Wilson, M; Neveu, V; Tang, A; Gabriel, G; Ly, C; Adamjee, S; Dame, ZT; Han, B; Zhou, Y; Wishart, DS. "Picrotoxin". DrugBank. DrugBank. Retrieved April 26, 2017.
  13. ^ Olsen, Richard (2006). "Picrotoxin-like channel blockers of GABAA receptors". Proceedings of the National Academy of Sciences of the United States of America. 103 (16): 6081–6082. doi:10.1073/pnas.0601121103. PMC 1458832. PMID 16606858. Retrieved April 26, 2017.
  14. ^ Newland, C F; Cull-Candy, S G (February 1992). "On the mechanism of action of picrotoxin on GABA receptor channels in dissociated sympathetic neurones of the rat". The Journal of Physiology. 447: 191–213. doi:10.1113/jphysiol.1992.sp018998. PMC 1176032. PMID 1317428.
  15. ^ "Picrotoxin" (PDF). Santa Cruz Biotechnology. Retrieved April 26, 2017.
  16. ^ "Picrotoxin". Toxnet. U.S. National Laboratory of Medicine. Retrieved April 26, 2017.
  17. ^ Nilsson, E.; Eyrich, B. (1950). "On Treatment of Barbiturate Poisoning". Acta Medica Scandinavica. 137 (6): 381–389. doi:10.1111/j.0954-6820.1950.tb12129.x. PMID 15432128
  18. ^ "Uniform Classification Guidelines for Foreign Substances and Recommended Penalties and Model Rule" (PDF). Association of Racing Commissioners International, Inc. Retrieved April 26, 2017.
  19. ^ Lemoreaux, Patrick (September 2, 2017). "Two Quarter Horse trainers suspended for drug violations at Prairie Meadows". Daily Racing Form. Daily Racing Form. Retrieved April 26, 2017.

Further reading

  • Ehrenberger, K.; Benkoe, E.; Felix, D. (1982). "Suppressive Action of Picrotoxin, a GABA Antagonist, on Labyrinthine Spontaneous Nystagmus and Vertigo in Man". Acta Oto-Laryngologica. 93 (3–4): 269–273. doi:10.3109/00016488209130882. PMID 7064710.
  • Dupont, L.; Dideberg, O.; Lamotte-Brasseur, J.; Angenot, L. (1976). "Structure cristalline et moléculaire de la picrotoxine, C15H16O6·C15H18O7". Acta Crystallographica B (in French). 32 (11): 2987–2993. doi:10.1107/S0567740876009424.
  • Olsen, R. W.; DeLorey, T. M. (1999). "GABA Receptor Physiology and Pharmacology". In Siegel G. J.; Agranoff, B. W.; Albers, R. W.; et al. (eds.). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Philadelphia, PA, USA: Lippincott-Raven.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Picrotoxin&oldid=873022419"