Ibotenic acid

Last updated

Ibotenic acid
Ibotenic acid2.png
Ibotenic acid 3D structure.png
Names
IUPAC name
(S)-2-Amino-2-(3-hydroxyisoxazol-5-yl)acetic acid
Other names
Ibotenic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.151.170 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 622-405-7
KEGG
PubChem CID
UNII
  • InChI=1S/C5H6N2O4/c6-4(5(9)10)2-1-3(8)7-11-2/h1,4H,6H2,(H,7,8)(H,9,10) Yes check.svgY
    Key: IRJCBFDCFXCWGO-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C5H6N2O4/c6-4(5(9)10)2-1-3(8)7-11-2/h1,4H,6H2,(H,7,8)(H,9,10)
    Key: IRJCBFDCFXCWGO-UHFFFAOYAQ
  • (S)-:Key: IRJCBFDCFXCWGO-BYPYZUCNSA-N
  • O=C1/C=C(\ON1)C(C(=O)O)N
Properties
C5H6N2O4
Molar mass 158.113 g·mol−1
Melting point 151-152 °C (anhydrous)
144-146 °C (monohydrate)
H2O: 1 mg/mL
0.1 M NaOH: 10.7 mg/mL
0.1 M HCl: 4.7 mg/mL
Hazards
GHS labelling: [1]
GHS-pictogram-skull.svg
Danger
H301
P264, P270, P301+P316, P321, P330, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Ibotenic acid or (S)-2-amino-2-(3-hydroxyisoxazol-5-yl)acetic acid, also referred to as ibotenate, is a chemical compound and psychoactive drug which occurs naturally in Amanita muscaria and related species of mushrooms typically found in the temperate and boreal regions of the northern hemisphere. It is a prodrug of muscimol, broken down by the liver to that much more stable compound. [2] It is a conformationally-restricted analogue of the neurotransmitter glutamate, and due to its structural similarity to this neurotransmitter, acts as a non-selective glutamate receptor agonist. [3] Because of this, ibotenic acid can be a powerful neurotoxin in high doses, and is employed as a "brain-lesioning agent" through cranial injections in scientific research. [4] [5] The neurotoxic effects appear to be dose-related and risks are unclear through consumption of ibotenic-acid containing fungi, although thought to be negligible in small doses. [6] [ better source needed ]

Contents

Pharmacology

Amanita muscaria, which contains ibotenic acid Amanita muscaria 3 vliegenzwammen op rij.jpg
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. [3] [7] It is inactive at group III mGluRs. [8] Ibotenic acid also acts as a weak agonist of the AMPA and kainate receptors. [3] [7] In addition, due to in vivo decarboxylation into muscimol, it acts indirectly as a potent GABAA and GABAA-ρ receptor agonist. [7] 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. [9] [10]

Biological properties

Mechanism of action

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. [11]

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 Activated NMDAR.svg
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. [12]

Biological effects

Ibotenic acid typically affects both NMDA and APCD or metabolotropic quisqualate receptor sites in the central nervous system. [11] 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. [13] 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. [14]

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. [14]

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. [15]

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. [16]

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. [17]

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. [18]

See also

Related Research Articles

<i>Amanita muscaria</i> Species of mushroom

Amanita muscaria, commonly known as the fly agaric or fly amanita, is a basidiomycete of the genus Amanita. It is a large white-gilled, white-spotted, and usually red mushroom.

<i>N</i>-Methyl-<small>D</small>-aspartic acid Amino acid derivative

N-methyl-D-aspartic acid or N-methyl-D-aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors. NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

<i>Amanita pantherina</i> Species of fungus

Amanita pantherina, also known as the panther cap, false blusher, and the panther amanita due to its similarity to the true blusher, is a species of fungus found in Eurasia with poisonous and psychoactive properties.

<span class="mw-page-title-main">Muscimol</span> Neurotransmission inhibitor

Muscimol is a potent psychoactive compound found in certain mushrooms, most notably the Amanita muscaria and related species of mushroom. Muscimol is a potent and selective orthosteric agonist for the GABAA receptor.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

<span class="mw-page-title-main">Kainic acid</span> Chemical compound

Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervous system. Glutamate is produced by the cell's metabolic processes and there are four major classifications of glutamate receptors: NMDA receptors, AMPA receptors, kainate receptors, and the metabotropic glutamate receptors. Kainic acid is an agonist for kainate receptors, a type of ionotropic glutamate receptor. Kainate receptors likely control a sodium channel that produces excitatory postsynaptic potentials (EPSPs) when glutamate binds.

<span class="mw-page-title-main">Metabotropic glutamate receptor</span> Type of glutamate receptor

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">Quisqualic acid</span> Chemical compound

Quisqualic acid is an agonist of the AMPA, kainate, and group I metabotropic glutamate receptors. It is one of the most potent AMPA receptor agonists known. It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord. Quisqualic acid occurs naturally in the seeds of Quisqualis species.

<i>N</i>-Acetylaspartylglutamic acid Peptide neurotransmitter

N-Acetylaspartylglutamic acid is a peptide neurotransmitter and the third-most-prevalent neurotransmitter in the mammalian nervous system. NAAG consists of N-acetylaspartic acid (NAA) and glutamic acid coupled via a peptide bond.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

<span class="mw-page-title-main">Eglumetad</span> Chemical compound

Eglumetad is a research drug developed by Eli Lilly and Company, which is being investigated for its potential in the treatment of anxiety and drug addiction. It is a glutamate derived compound and its mode of action implies a novel mechanism.

The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms of schizophrenia linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.

<span class="mw-page-title-main">Amanita muscaria var. guessowii</span> Variety of fungi

Amanita chrysoblema yellow-orange variant, commonly known as the American yellow fly agaric, is a basidiomycete fungus of the genus Amanita. It is one of several varieties of muscaroid fungi, all commonly known as fly agarics or fly amanitas.

<span class="mw-page-title-main">LY-379,268</span> Chemical compound

LY-379,268 is a drug that is used in neuroscience research, which acts as a potent and selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).

<i>Amanita muscaria <span style="font-style:normal;">var.</span> formosa</i> Species of fungus

Amanita muscaria var. formosa, known as the yellow orange fly agaric, is a hallucinogenic and poisonous basidiomycete fungus of the genus Amanita. This variety, which can sometimes be distinguished from most other A. muscaria by its yellow cap, is a European taxon, although several North American field guides have referred A. muscaria var. guessowii to this name. American mycologist Harry D. Thiers described a yellow-capped taxon that he called var. formosa from the United States, but it is not the same as the European variety. The Amanita Muscaria is native to temperate or boreal forest regions of the Northern Hemisphere. However, it has also been introduced in New Zealand, Australia, South America, and South Africa.

<span class="mw-page-title-main">Willardiine</span> Chemical compound

Willardiine (correctly spelled with two successive i's) or (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione is a chemical compound that occurs naturally in the seeds of Mariosousa willardiana and Acacia sensu lato. The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See:#Synthesis). Willardiine is frequently studied for its function in higher level plants. Additionally, many derivates of willardiine are researched for their potential in pharmaceutical development. Willardiine was first discovered in 1959 by R. Gmelin, when he isolated several free, non-protein amino acids from Acacia willardiana (another name for Mariosousa willardiana) when he was studying how these families of plants synthesize uracilyalanines. A related compound, Isowillardiine, was concurrently isolated by a different group, and it was discovered that the two compounds had different structural and functional properties. Subsequent research on willardiine has focused on the functional significance of different substitutions at the nitrogen group and the development of analogs of willardiine with different pharmacokinetic properties. In general, Willardiine is the one of the first compounds studied in which slight changes to molecular structure result in compounds with significantly different pharmacokinetic properties.

<i>Amanita muscaria <span style="font-style:normal;">var.</span> inzengae</i> Species of fungus

Amanita muscaria var. inzengae, commonly known as Inzenga's fly agaric, is a basidiomycete fungus of the genus Amanita. It is one of several varieties of the Amanita muscaria fungi, all commonly known as fly agarics or fly amanitas.

References

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