Chemistry:Ibotenic acid

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Short description: Naturally occurring glutamate receptor agonist neurotoxin

Not to be confused with Ibogaine, a different psychoactive compound.
Ibotenic acid
Clinical data
Other namesIbotenic acid; Ibotenate; Premuscimol
Routes of
administration		Oral
Drug classNMDA receptor agonist; Metabotropic glutamate receptor agonist; GABAA receptor agonist; Neurotoxin; Hallucinogen
ATC code
  • None
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC5H6N2O4
Molar mass158.113 g·mol−1
3D model (JSmol)
Melting point151 to 152 °C (304 to 306 °F) °C (anhydrous)
144-146 °C (monohydrate)
Solubility in waterH2O: 1 mg/mL
0.1 M NaOH: 10.7 mg/mL
0.1 M HCl: 4.7 mg/mL mg/mL (20 °C)
  (verify)

Ibotenic acid, or ibotenate, also known as premuscimol or as (S)-2-amino-2-(3-hydroxyisoxazol-5-yl)acetic acid, is a naturally occurring α-amino acid found in certain Amanita mushrooms such as Amanita muscaria.[1][2][3][4] It acts primarily as a potent glutamate receptor agonist and produces neurological effects.[1][2][3][4] The compound is used as a brain-lesioning agent in scientific research.[5]

Ibotenic acid is a conformationally-restricted analogue of the excitatory neurotransmitter glutamate which acts as a non-selective agonist of glutamate receptors, strongly activating NMDA, group I and II metabotropic glutamate receptors, and weakly activating AMPA and kainate receptors. Taken systemically, it is a prodrug of muscimol, broken down by the liver into this more stable compound, which acts as a potent GABAA and GABAA-ρ receptor agonist. Although the compound's psychoactive effects are not well-understood, some researchers speculate that ibotenic acid itself may have stimulant-like properties. Ibotenic acid is biosynthesized from glutamic acid by hydroxylation catalyzed by an Fe(II)/2-oxoglutarate-dependent oxygenase, with subsequent conversion steps carried out by enzymes encoded within a linked biosynthetic gene cluster.

Ibotenic acid is commonly used in research to create site-specific hippocampal brain lesions in rats, allowing for task relearning due to its interaction with glutamate receptors, and is favored over other agents for its selectivity and long-term stability in saline solution.[6][7] It induces excitotoxicity in rodents by overactivating NMDA and metabotropic glutamate receptors, leading to calcium overload and oxidative damage. In contrast, it targets glutamate-gated chloride channels in invertebrates, causing increased chloride permeability without affecting their excitatory glutamate receptors.[8][9]

Biological properties

Mechanism of action

Amanita muscaria, which contains ibotenic acid.

Ibotenic acid acts as a potent agonist of the NMDA and group I (mGluR1 and mGluR5) and II (mGluR2 and mGluR3) metabotropic glutamate receptors.[10][11] It is inactive at group III mGluRs.[12] Ibotenic acid also acts as a weak agonist of the AMPA and kainate receptors.[10][11] In addition, due to in vivo decarboxylation into muscimol, it acts indirectly as a potent GABAA and GABAA-ρ receptor agonist.[11] Unlike muscimol—the principal psychoactive constituent of Amanita muscaria that is understood to cause sedation and delirium—ibotenic acid's psychoactive effects are not known independent of its serving as a prodrug to muscimol, although some researchers have speculated that it would act as a stimulant.[13][14][15]

Ibotenic acid is an agonist of glutamate receptors, specifically at both the N-methyl-D-aspartate, or NMDA, and trans-ACPD receptor sites in multiple systems in the central nervous system. Ibotenic neurotoxicity can be enhanced by glycine and blocked by dizocilpine. Dizocilpine acts as an uncompetitive antagonist at NMDA receptors.[16]

Ibotenic acid toxicity comes from activation of the NMDA receptors. NMDA receptors are related to synaptic plasticity and work with metabotropic glutamate receptors to establish long term potentiation or LTP. The process of long term potentiation is believed to be related to the acquisition of information. The NMDA receptor functions properly by allowing Ca2+ ions to pass through after activation at the receptor site.

Activated NMDAR

The binding of ibotenic acid allows excess Ca2+ into the system which results in neuronal cell death. Ca2+ also activates CaM-KII or Ca2+/Calmodulin Kinase which phosphorylates multiple enzymes. The activated enzymes then begin producing reactive oxygen species which damages surrounding tissue. The excess Ca2+ results in the enhancement of the mitochondrial electron transport system which will further increase the number of reactive oxygen species.[17]

Biological effects

Ibotenic acid typically affects both NMDA and APCD or metabolotropic quisqualate receptor sites in the central nervous system.[16] Due to their targeting of these systems the symptoms associated with ibotenic acid poisoning are often related to perception and control.

At least some ingested ibotenic acid is likely decarboxylated into muscimol so some of the effects of ingesting ibotenic acid are similar to muscimol's effects.[1] Symptoms associated with ibotenic acid are usually onset within 30–60 minutes and include a range of nervous system effects. The most common symptoms include nausea, vomiting, and drowsiness. However, after the first hour symptoms begin to include confusion, euphoria, visual and auditory distortions, sensations of floating, and retrograde amnesia.[18]

Symptoms are slightly different for children, typically beginning after 30–180 minutes. Dominant symptoms in children include ataxia, obtundation, and lethargy. Seizures are occasionally reported, however, more commonly with children.[18]

In contrast, ibotenic acid has a completely different action in invertebrates. Instead of an excitatory effect, it increases the permeability of invertebrate skeletal muscle and nerve cell membranes to chloride ions but shows no affinity for invertebrate glutamate excitatory receptors. This effect was first observed in locust muscle fibers,[8][9][19] leading to the discovery of a new ion channel, the glutamate-gated chloride channel (GluCl), which was later cloned from the soil nematode C. elegans.[20]Similar effects have been observed in other invertebrate excitable cells, including Drosophila melanogaster neurons and crayfish muscle.[21][22]

Since GluCl does not exist in vertebrates, it has become a valuable target for anti-parasitic drugs such as Avermectin and Ivermectin.[21][22][23]

Treatment

Treatment of ibotenic acid toxicity centres around supportive care and treatment of symptoms; no antidote is available. Gastric decontamination with activated charcoal or gastric lavage can be of benefit if the patient presents early. The psychotropic effects and hallucinations ibotenic acid and its metabolite muscimol produce are best managed in a quiet environment with minimal stimulation. Benzodiazepines can be of benefit in agitated or panicked patients; they can also be used to control seizures if they occur. Benzodiazepines as a GABA-A PAM interacts with Muscimol as a GABA-A agonist and may cause a significantly increased risk of depressant effects. Airway management may be required if sedation is profound. Symptoms usually resolve within a few hours of ingestion but can last for days following significant exposures.[24]

Monitoring for the presence of brain lesions may be required following a large or repeated exposure. Other measures may be required if the patient has been exposed to a mushroom such as Amanita muscaria as other active compounds may be present.[1]

Use in research

Ibotenic acid used for the lesioning of rat's brains is kept frozen in a phosphate-buffered Saline Solution at a pH of 7.4, and can be kept for up to a year with no loss in toxicity. Injection of .05-.1 microliters of Ibotenic acid into the hippocampus at a rate of .1 microliter/min resulted in semi-selective lesioning. Hippocampal lesioning led to a considerable loss of cells in pyramidal cells (CA1-CA3) as well as granule cells in the dentate gyrus. Ibotenic acid lesioning also causes some damage to axons along the perforant pathway.

Typically, when lesioning is done with other chemicals the subject cannot relearn a task. However, due to Ibotenic acid's reactivity with glutamate receptors such as the NMDA receptor, Ibotenic acid lesioning does allow the subject to relearn tasks. Ibotenic acid lesioning is thus preferred in studies where re-learning a task after lesioning is essential. Compared to other lesioning agents, Ibotenic acid is one of the most site-specific; however, less-damaging alternatives are presently sought.[25]

Biosynthesis

Ibotenic acid's biosynthetic genes are organized in a physically linked biosynthetic gene cluster. The biosynthetic pathway is initiated by hydroxylation of glutamic acid by a dedicated Fe(II)/2-oxoglutarate-dependent oxygenase. The reaction yields threo-3-hydroxyglutamic acid, which is converted into ibotenic acid, likely by enzymes encoded in the biosynthetic gene cluster.[26]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "Amanita muscaria: chemistry, biology, toxicology, and ethnomycology". Mycological Research 107 (Pt 2): 131–146. February 2003. doi:10.1017/s0953756203007305. PMID 12747324. 
  2. ↑ 2.0 2.1 "Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities". Therapeutic Drug Monitoring 35 (4): 420–442. August 2013. doi:10.1097/FTD.0b013e31828741a5. PMID 23851905. 
  3. ↑ 3.0 3.1 "Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties". International Journal of Medicinal Mushrooms 25 (9): 1–10. 2023. doi:10.1615/IntJMedMushrooms.2023049458. PMID 37824402. 
  4. ↑ 4.0 4.1 "Naturally-occurring excitatory amino acids as neurotoxins and leads in drug design". Toxicology Letters 64-65 Spec No: 409–416. December 1992. doi:10.1016/0378-4274(92)90214-5. PMID 1335179. 
  5. ↑ "Gaboxadol, by Hamilton Morris". 18 June 2021. https://harpers.org/archive/2013/08/gaboxadol/. 
  6. ↑ "Social behaviour in rats lesioned with ibotenic acid in the hippocampus: quantitative and qualitative analysis". Psychopharmacology 144 (4): 333–338. June 1999. doi:10.1007/s002130051015. PMID 10435405. 
  7. ↑ "Functional neuronal replacement by grafted striatal neurones in the ibotenic acid-lesioned rat striatum". Nature 311 (5985): 458–460. 1984. doi:10.1038/311458a0. PMID 6482962. Bibcode: 1984Natur.311..458I. 
  8. ↑ 8.0 8.1 "The site of action of ibotenic acid and the identification of two populations of glutamate receptors on insect muscle-fibres". Comparative and General Pharmacology 4 (16): 333–350. December 1973. doi:10.1016/0010-4035(73)90045-1. PMID 4799403. 
  9. ↑ 9.0 9.1 "Effect of ibotenic acid on chloride permeability of insect muscle-fibres". Comparative and General Pharmacology 4 (16): 351–363. December 1973. doi:10.1016/0010-4035(73)90046-3. PMID 4799404. 
  10. ↑ 10.0 10.1 Textbook of Drug Design and Discovery, Third Edition. CRC Press. 25 July 2002. pp. 263–. ISBN 978-0-415-28288-8. https://books.google.com/books?id=EL-UI6t8omQC&pg=PA263. 
  11. ↑ 11.0 11.1 11.2 Pharmacological Research on Traditional Herbal Medicines. CRC Press. 23 July 1999. pp. 107–. ISBN 978-90-5702-054-4. https://books.google.com/books?id=UExUOKw3EwYC&pg=PA107. 
  12. ↑ "Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors". European Journal of Pharmacology 486 (3): 241–250. February 2004. doi:10.1016/j.ejphar.2003.12.033. PMID 14985045. 
  13. ↑ "The course of an intentional poisoning". McIlvainea 2: 17–18. 1975. https://namyco.org/wp-content/uploads/2023/08/McIlvainea_Vol_2.pdf. 
  14. ↑ "[Pharmacological and experimental psychological studies with 2 components of fly agaric (Amanita muscaria)]" (in German). Arzneimittel-Forschung 18 (3): 311–5. March 1968. PMID 5696006. 
  15. ↑ "Toxic metabolites of Amanita pantherina, A. cothurnata, A. muscaria and other Amanita species". Lloydia 39 (2–3): 150–7. 1976. PMID 985999. 
  16. ↑ 16.0 16.1 "Ibotenic acid mediates neurotoxicity and phosphoinositide hydrolysis by independent receptor mechanisms". Molecular and Chemical Neuropathology 16 (1–2): 1–10. February 1992. doi:10.1007/bf03159956. PMID 1325800. 
  17. ↑ "Excitotoxicity and the NMDA receptor". http://www.eurosiva.org/archive/vienna/abstracts/speakers/sureda.htm. 
  18. ↑ 18.0 18.1 "Symptoms of ibotenic/muscimol poisoning (isoxazol poisoning)". MykoWeb. http://www.mykoweb.com/TFWNA/P-28.html. 
  19. ↑ "Two populations of L-glutamate receptors on locust muscle fibres". Nature 246 (150): 62–64. November 1973. doi:10.1038/newbio246062a0. PMID 4519031. 
  20. ↑ "Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans". Nature 371 (6499): 707–711. October 1994. doi:10.1038/371707a0. PMID 7935817. Bibcode: 1994Natur.371..707C. 
  21. ↑ 21.0 21.1 "Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin". The Journal of Biological Chemistry 271 (33): 20187–20191. August 1996. doi:10.1074/jbc.271.33.20187. PMID 8702744. 
  22. ↑ 22.0 22.1 "The insecticide avermectin b (la) activates a chloride channel in crayfish muscle membrane". The Journal of Experimental Biology 142 (1): 191–205. March 1989. doi:10.1242/jeb.142.1.191. PMID 22135837. Bibcode: 1989JExpB.142..191Z. 
  23. ↑ "Glutamate-gated Chloride Channels" (in en). https://www.researchgate.net/publication/232087717. 
  24. ↑ "Hallucinogenic Mushroom Toxicity". http://emedicine.medscape.com/article/817848-overview. 
  25. ↑ "On the use of ibotenic acid to lesion selectively different components of the hippocampal formation". Journal of Neuroscience Methods 29 (3): 251–259. September 1989. doi:10.1016/0165-0270(89)90149-0. PMID 2477650. 
  26. ↑ "Ibotenic Acid Biosynthesis in the Fly Agaric Is Initiated by Glutamate Hydroxylation". Angewandte Chemie 59 (30): 12432–12435. July 2020. doi:10.1002/anie.202001870. PMID 32233056. Bibcode: 2020ACIE...5912432O. 

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