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Muscimol

"Pantherine" redirects here. For the cat subfamily, see Pantherinae.

Muscimol
Names
IUPAC name
5-(Aminomethyl)-1,2-oxazol-3(2H)-one
Other names
Agarin, Pantherine, Agarine, Pantherin
Identifiers
3D model (JSmol)
774694
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.018.574 Edit this at Wikidata
EC Number
  • 220-430-4
KEGG
UNII
UN number 2811 3077
  • InChI=1S/C4H6N2O2/c5-2-3-1-4(7)6-8-3/h1H,2,5H2,(H,6,7) checkY
    Key: ZJQHPWUVQPJPQT-UHFFFAOYSA-N checkY
  • InChI=1/C4H6N2O2/c5-2-3-1-4(7)6-8-3/h1H,2,5H2,(H,6,7)
    Key: ZJQHPWUVQPJPQT-UHFFFAOYAI
  • NCc1cc(no1)O
Properties[1]
C4H6N2O2
Molar mass 114.104 g·mol−1
Melting point 184 to 185 °C (363 to 365 °F; 457 to 458 K)
very soluble
Solubility in ethanol slightly soluble
Solubility in methanol very soluble
Pharmacology
Legal status
  • AU: S9 (Prohibited substance)
  • in general, uncontrolled
Hazards
GHS labelling:[2]
H300
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).
☒N verify (what is checkY☒N ?)

Muscimol (also known as agarin or pantherine) is one of the principal psychoactive constituents of Amanita muscaria and related species of mushroom. Muscimol is a potent and selective orthosteric agonist for the GABAA receptor[3] and displays sedative-hypnotic, depressant and hallucinogenic[citation needed] psychoactivity. This colorless or white solid is classified as an isoxazole.

Muscimol underwent a phase I clinical trial for epilepsy, but the trial was discontinued.[4]

Muscimol, an agonist for the GABAA receptor, was able to significantly alleviate pain in its peak effect, recent studies from 2023 show. It has since been federally banned in Australia and is pending FDA review in the United States, but scientists believe it may relieve pain as well as some opioids without much of the risk of addiction associated with opioids. [5]

Biochemistry

The main natural sources of muscimol are fungi of the genus Amanita, such as Amanita muscaria (fly agaric) and Amanita pantherina (panther amanita). It is produced in the mushrooms along with muscarine (which is present in trace amounts and it is not active), muscazone, and ibotenic acid.[6][7] In A. muscaria, the layer just below the skin of the cap contains the highest amount of muscimol, and is therefore the most psychoactive portion.[8]

Muscimol is recognized as a potent agonist for ionotropic GABA-A receptors. By mimicking the inhibitory neurotransmitter GABA, muscimol activates these receptors, leading to the opening of chloride channels and subsequent hyperpolarization of neurons. This results in decreased neuronal excitability, which is crucial for maintaining the balance between excitation and inhibition in the central nervous system.[9]

The biochemical properties of muscimol make it a valuable tool for investigating GABAergic mechanisms. Its high affinity and specificity for GABA-A receptors allow researchers to study synaptic transmission, neural circuit dynamics, and the overall role of GABAergic inhibition in various physiological and pathological states.[9]

Amanita muscaria, which contains muscimol

Pharmacology

GABA and muscimol molecules can have similar 3D-conformations which are shown superimposed in this image. Because of this similarity, muscimol binds to certain GABA-receptors.[7]

Muscimol is a potent GABAA agonist, activating the receptor for the brain's principal inhibitory neurotransmitter, GABA. Muscimol binds to the same site on the GABAA receptor complex as GABA itself, as opposed to other GABAergic drugs such as barbiturates and benzodiazepines which bind to separate regulatory sites.[10] GABAA receptors are widely distributed in the brain, and so when muscimol is administered, it alters neuronal activity in multiple regions including the cerebral cortex, hippocampus, and cerebellum. While muscimol is normally thought of as a selective GABAA agonist with exceptionally high affinity to GABAA-delta receptors,[11][12][13] it is also a partial agonist at the GABAA-rho receptor, and so its range of effects results from a combined action on more than one GABAA receptor subtype.[14]

Scientific studies have shown that dosing of the active ingredient muscimol is usually not precise as it has to be extracted from dried amanita mushroom. However, a psychoactive dose of muscimol is reported to be between 8 and 15 mg. As little as a gram of dried Amanita muscaria button may contain this amount of muscimol; however, the potency varies greatly among mushrooms.[15]

When consumed, a substantial percentage of muscimol goes un-metabolized and thus excreted in urine, a phenomenon exploited by Siberian practitioners of the traditional entheogenic use of Amanita muscaria.[16]

In patients with Huntington's disease and chronic schizophrenia, oral doses of muscimol have been found to cause a rise of both prolactin and growth hormone.[17]

During a test involving rabbits connected to an EEG, muscimol presented with a distinctly synchronized EEG tracing. This is substantially different from serotonergic psychedelics, with which brainwave patterns generally show a desynchronization. In higher doses (2 mg/kg via IV), the EEG will show characteristic spikes.[18]

Mechanism of action

Muscimol primarily functions as a GABA-A receptor agonist, mimicking the action of GABA, the main inhibitory neurotransmitter, in the central nervous system.

Effects

Muscimol, as a GABA-A receptor agonist, has shown diverse pharmacological effects, spanning neuroprotective, anti-nociceptive, and anti-epileptic activity.[19]


Recent research has highlighted the following effects of muscimol:

Clinical research

Muscimol underwent a phase I clinical trial for epilepsy in 2012, but this trial was discontinued.[4]

A handful of exploratory clinical trials (n≤10) probing the utility of muscimol in the treatment of schizophrenia, Huntington's disease, and tardive dyskinesia occurred between 1977-1982.[28][29][30] The clinical investigation of muscimol in these conditions was superseded by gaboxadol, a conformationally constrained derivative of muscimol.[31] Neither drug appeared to be efficacious in the treatment of Huntington's disease or L-dopa/neuroleptic induced dyskinesia.[32][33]

Muscimol-based products

Muscimol, a psychoactive compound derived from the ibotenic acid found in certain mushrooms, particularly Amanita muscaria, has garnered significant interest due to its unique effects on the nervous system. Muscimol binds to GABA receptors in the brain, resulting in its sedative and hallucinogenic properties.[citation needed] Muscimol-based products are currently being investigated for their potential therapeutic applications, especially in the treatment of anxiety, insomnia, and other neurological disorders.[34][35] The psychoactive nature of muscimol necessitates stringent regulation and cautious usage to ensure safety.[36] However, ongoing research aims to harness its medicinal benefits in a controlled context, highlighting the broader scientific interest in natural compounds as potential sources for novel medical treatments.[citation needed]

Chemistry

Structure

Muscimol was first isolated from Amanita pantherina by Onda in 1964,[37] and thought to be an amino acid or peptide. Structure was then elucidated by Takemoto,[38] Eugster,[39] and Bowden.[40] Muscimol is a semi-rigid isoxazole containing both alcohol and aminomethyl substituents.[41] Muscimol is commonly portrayed as a tautomer, where it adopts an amide-like configuration.[2] It is also commonly shown as a zwitterion.[42]

Isolation

Muscimol can be extracted from the flesh of the Amanita muscaria by treatment with boiling water, followed by rapid cooling, and further treatment with a basic resin. This is washed with water, and eluted with acetic acid using column chromatography. The eluate is freeze dried, dissolved in water, and passed down a column of cellulose phosphate.[43] A subsequent elution with ammonium hydroxide and recrystallization from alcohol results in pure muscimol.[44]

In instances where pure muscimol is not required, such as recreational or spiritual use, a crude extract is often prepared by simmering dried Amanita muscaria in water for thirty minutes.[45]

Chemical synthesis

Muscimol was synthesized in 1965 by Gagneux,[46] who utilized a bromo-isoxazole starting material in a two step reaction. 3-bromo-5-aminomethyl-isoxazole (1) was refluxed in a mixture of methanol and potassium hydroxide for 30 hours, resulting in 3-methoxy-5-aminomethyl-isoxazole (2) with a yield of 60%.

(2) was then refluxed in concentrated hydrochloric acid to hydrolyze the methoxy group, and the zwitterion crystallized from a solution of methanol and tetrahydrofuran after the addition of triethylamine, resulting in a 50% yield.[46]

Chemists report having struggled to reproduce these results.[47][48] More dependable and scalable procedures have been developed, two examples being the syntheses of McCarry[49] and Varasi.[42]

McCarry's synthesis is a three step synthesis involving a lithium acetylide produced from propargyl chloride. The acetylide (3), was dissolved in ether, cooled to -40 °C, and treated with excess ethyl chloroformate to afford ethyl 4-chlorotetrolate (4) in a 70% yield. (4) was then added to a solution of water, methanol and hydroxylamine at -35 °C. At a pH of between 8.5 and 9, the isoxazole (5) was recovered in a 41% yield. Muscimol was formed in a 65% yield when (5) was dissolved in a saturated solution of methanol and anhydrous ammonia and heated from 0 °C to 50 °C. The total yield was 18.7%.[49]

Varasi's synthesis is notable for its inexpensive starting materials and mild conditions. It begins with the combination of 2,3-Dichloro-1-propene (6), potassium bicarbonate, water, and dibromoformaldoxime (7) (which is a well known precursor of bromo nitriloxyde, a reactive dipole for regioselective Diels-Alder cycloadditions, which forms in alkali), all dissolved in ethyl acetate. 5-Chloromethyl-3-bromoisoxazole (8) was extracted with an experimental yield of 81%. 5-Aminomethyl-3-bromoisoxazole (9) was formed in 90% yield by the combination of (8) and ammonium hydroxide in dioxane.[42]

(9) was then refluxed with potassium hydroxide in methanol to generate 5-Aminomethyl-3-methoxyisoxazole (10) with a 66% yield. Subsequent reflux of (10) with hydrobromic acid and acetic acid generated muscimol with a yield of 62%. The overall synthetic yield was 30%.[42]

Toxicity

The toxicity and safety profile of Muscimol have been studied in various contexts, both experimental and clinical.

Dose-Dependent Effects in Primates

A study on nonhuman primates indicated that muscimol, when administered in escalating doses, caused reversible hyperkinesia and dyskinesias at higher doses (up to 88.8 mM), but no long-term toxicity was observed on histological examination.[50]

The median lethal dose in mice is 3.8 mg/kg s.c, 2.5 mg/kg i.p. The LD50 in rats is 4.5 mg/kg i.v, 45 mg/kg orally.[51]

Anticonvulsant Properties

Muscimol has shown potential as an anticonvulsant, blocking seizures induced by various agents in animal models without causing significant toxicity at therapeutic doses.[52]

Human Poisoning Cases

A retrospective review of muscimol poisoning cases from Amanita mushrooms indicated that symptoms included gastrointestinal upset, CNS excitation, but no deaths were reported. Most symptoms resolved within 24 hours.[53]

Distribution and Metabolism

Studies on muscimol's distribution in rats showed it enters the brain and is metabolized rapidly, suggesting that its toxicity is low when used in controlled doses.[citation needed]

Muscimol exhibits dose-dependent effects with higher doses leading to significant, but reversible, CNS symptoms.[54] Its toxicity appears to be low when used in controlled environments, with no long-term damage observed in animal studies and human cases resolving without severe outcomes. However, caution is advised with its use due to its potent effects on the central nervous system.[citation needed]

Australia

Muscimol is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). A Schedule 9 substance is a substance "which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities."[55]

United States

Neither Amanita muscaria nor muscimol is considered a controlled substance by the Federal government of the United States. This means that cultivation, possession, and distribution are unregulated by the United States Federal Government.[56][57] The legality of Amanita muscaria and muscimol as ingredients in food is unclear since neither are approved as food additives by the FDA. However, agriculture regulators in Florida actioned against one seller of Amanita products after the agency had determined such products were considered adulterated under state law.[58]

Muscimol may be regulated on a state level. Louisiana State Act 159 banned the possession and cultivation of the Amanita muscaria except for ornamental or aesthetic purposes. Except as a constituent of lawfully manufactured food or dietary supplements, the act outlaws preparations of the Amanita muscaria intended for human consumption, including muscimol.[59]

See also

References

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