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Muscimol

From Wikipedia, the free encyclopedia
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
  • legal in most countries
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 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[3].

Muscimol, an agonist for the GABAA receptor, was able to significantly alleviate pain in its peak effect, recent studies from 2023 show. Muscimol, through its potent interaction with GABA-A receptors, exerts significant effects on the central nervous system. Its ability to enhance inhibitory neurotransmission and protect neurons from excitotoxic damage makes it a compound of great interest in neuropharmacology. The diverse pharmacological effects of muscimol, from neuroprotection and pain relief to cognitive modulation and anticonvulsant properties, underscore its therapeutic potential across a range of neurological and psychiatric disorders [4]. Ongoing research continues to explore and expand upon the applications of muscimol in medicine.

Biochemistry[edit]

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.[5][6] 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.[7]

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.[8]

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[edit]

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.[6]

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[edit]

Muscimol primarily functions as a GABA-A receptor agonist, meaning it mimics the action of GABA, the main inhibitory neurotransmitter in the central nervous system. By binding to GABA-A receptors, muscimol increases the inhibitory effects of GABA, leading to hyperpolarization of neurons and decreased neuronal excitability. The mechanism of action involves the following steps:

1.Binding: Muscimol binds to the same sites on the GABA-A receptor as GABA. These receptors are pentameric structures composed of various subunits that form a central chloride ion channel.[19]

2.Activation: Upon binding to the GABA-A receptor, muscimol induces a conformational change in the receptor, which opens the chloride ion channel.[20]

3.Chloride Ion Influx: The opening of the chloride channel allows chloride ions (Cl-) to flow into the neuron. This influx of negatively charged ions increases the negative charge inside the neuron, causing hyperpolarization of the neuronal membrane.[21]

4.Hyperpolarization: The hyperpolarization makes the neuron less likely to reach the threshold needed to trigger an action potential. This inhibitory effect reduces neuronal excitability and dampens the overall activity of neural circuits.[22]

Effects[edit]

Muscimol, as a GABA-A receptor agonist, has shown diverse pharmacological effects, from neuroprotection and pain management to influencing cognitive functions and treating epilepsy [23]

Ongoing research continues to uncover its potential therapeutic applications, making it a compound of significant interest in neuropharmacology.[24]

The recent researches on muscimol highlight the next effects:

Neurotransmission Modulation: By mimicking GABA and binding to GABA-A receptors, muscimol enhances inhibitory neurotransmission. This results in reduced neuronal firing rates, contributing to the overall calming effect on the CNS. This modulation is crucial in maintaining the balance between excitatory and inhibitory signals in the brain.[25]

Neuroprotective Effects: A recent study demonstrated the neuroprotective properties of muscimol. The research showed that muscimol, as part of the Shaoyao Gancao decoction, could mitigate excitatory damage in PC12 cells through the Src-NR2-nNOS pathway. [26]

Migraine and Headache: Studies on migraine models demonstrated that extrasynaptic GABA-A receptor agonists like muscimol could prevent migraine-like phenotypes, offering new avenues for migraine treatment. [27]

Depressant Effects: By enhancing inhibitory neurotransmission, muscimol acts as a CNS depressant. This can lead to muscle relaxation, reduction in anxiety.[28]

Antinociceptive Properties: Muscimol has been found to have antinociceptive effects when used in combination with citalopram, a selective serotonin reuptake inhibitor. This additive effect highlights muscimol's potential in pain management.[29]

Decision Making and Cognitive Function: Research on the role of the rat prelimbic cortex indicated that muscimol can influence decision-making processes. By infusing muscimol, researchers observed significant changes in cortical activity, which are crucial for understanding cognitive functions and cognitive disorders.[30]

Cerebral Ischemic Injury: Muscimol's role in alleviating cerebral ischemic injury was explored, revealing its ability to suppress oxidative stress, autophagy, and apoptosis pathways. This research underscores muscimol's potential in treating ischemic conditions.[31]

Pain Management: Activation of 5-HT5A receptors in the ventrolateral orbital cortex, alongside GABA-A receptor modulation by muscimol, showed significant antinociceptive effects in models of neuropathic pain and inflammatory pain.[32]

Epilepsy Models: In studies involving absence epilepsy models, muscimol demonstrated effects on T-type calcium channels and GABA receptors, providing insights into its anticonvulsant properties.[33]

Substance Use Disorders: Research into sex differences in GABA receptor regulation highlighted muscimol's potential in addressing cocaine use disorder, emphasizing its role in GABAergic modulation.[34]

Neurological Pathways: Investigations into neural pathways for internal bias and sensory information interaction in decision-making processes showed the significant impact of muscimol on visual cortex neurons.[35]

Muscimol and Anxiety[edit]

Muscimol, a potent GABA-A receptor agonist, has demonstrated significant anxiolytic properties. This compound, derived from the Amanita muscaria mushroom, effectively reduces anxiety by suppressing central nervous system activity. It enhances the inhibitory effects of GABA, the primary inhibitory neurotransmitter in the brain, leading to decreased neuronal excitability and a calming effect.[36]

Additionally, muscimol has been shown to increase dopamine levels in the brain. Dopamine is a neurotransmitter associated with pleasure and mood regulation. By boosting dopamine levels, muscimol not only alleviates anxiety but also enhances mood and promotes a sense of well-being. This dual effect makes muscimol a promising candidate for treating stress, anxiety, and related mood disorders.[37]

The therapeutic potential of muscimol lies in its ability to modulate the GABAergic system. GABA-A receptors play a crucial role in maintaining the balance between neuronal excitation and inhibition. By targeting these receptors, muscimol enhances the natural inhibitory mechanisms of the brain, leading to reduced anxiety and improved mood. This mechanism is similar to that of benzodiazepines, which are commonly prescribed for anxiety but come with a risk of dependence and side effects. Muscimol, on the other hand, offers a potentially safer alternative due to its natural origin and targeted action.[38]

The findings from studies on muscimol provide valuable insights into the development of new treatments for anxiety and mood disorders. As researchers continue to investigate its effects, there is hope for creating more effective and targeted therapies that leverage its unique properties. The increase in dopamine levels observed with muscimol treatment also suggests potential applications in treating conditions characterized by low dopamine, such as depression and certain mood disorders.[39]

Muscimol-Based Products[edit]

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.[40] Muscimol-based products are currently being investigated for their potential therapeutic applications, especially in the treatment of anxiety, insomnia, and other neurological disorders.[41][42] The psychoactive nature of muscimol necessitates stringent regulation and cautious usage to ensure safety.[43] 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.[44][45]

Chemistry[edit]

Chemical Formula: C_4H_6N_2O_2

Molecular Weight: 114.10 g/mol

Physical and Chemical Properties:

- Water Solubility: Muscimol is highly soluble in water.

- Melting Point: It has a melting point of 175-177°C.

- Appearance: Typically, muscimol appears as a white crystalline powder.

Structure[edit]

Muscimol was first isolated from Amanita pantherina by Onda in 1964,[46] and thought to be an amino acid or peptide. Structure was then elucidated by Takemoto,[47] Eugster,[48] and Bowden.[49] Muscimol is a semi-rigid isoxazole containing both alcohol and aminomethyl substituents.[50] Muscimol is commonly portrayed as a tautomer, where it adopts an amide-like configuration.[51] It is also commonly shown as a zwitterion.[52]

Isolation[edit]

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.[53] A subsequent elution with ammonium hydroxide and recrystallization from alcohol results in pure muscimol.[54]

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.[55]

Chemical synthesis[edit]

Muscimol was synthesized in 1965 by Gagneux,[56] 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.[56]

Chemists report having struggled to reproduce these results.[57][58] More dependable and scalable procedures have been developed, two examples being the syntheses of McCarry[59] and Varasi.[52]

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%.[59]

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), 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.[52]

(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%.[52]

Toxicity[edit]

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. [60]

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.[61]

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.[62]

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.[63]

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. [64]

Muscimol exhibits dose-dependent effects with higher doses leading to significant, but reversible, CNS symptoms.[65] 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.

Legal status[edit]

Australia[edit]

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."[66]

United States[edit]

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.[67][68] 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. [69]

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.[70]

See also[edit]

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External links[edit]

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