Muscimol
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| Surname | Muscimol | |||||||||||||||||||||
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| Molecular formula | C 4 H 6 N 2 O 2 | |||||||||||||||||||||
| Brief description |
colorless crystals |
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| properties | ||||||||||||||||||||||
| Molar mass | 114.10 g · mol -1 | |||||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
175 (decomposition) ° C |
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| pK s value |
4.8 and 8.4 |
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| solubility |
easily in water (567 g l −1 ) |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Muscimol is a psychotropic alkaloid that works by activating GABA receptors . It is produced by the decarboxylation of ibotenic acid , which is found in mushrooms of the genus Amanita .
General
Muscimol was discovered and isolated in the first half of the 1960s by several research groups independently of one another in the course of analytical work on the ingredients of the Amanita mushrooms . Its molecular structure was soon elucidated and confirmed by synthesis.
education
Ibotenic acid is the raw material contained in the toadstool , panther and king fly mushroom , from which muscimol is formed by decarboxylation under certain conditions, e.g. B. for longer storage of the mushroom or drying at about 60 ° C. It is better tolerated than its starting material and its hallucinogenic effects are significantly stronger.
effect
About two hours after ingestion, overdosing leads to increased salivation , ataxia , psychosis and finally circulatory failure . Because the amount of muscimol contained in mushrooms varies widely, it is not possible to predict whether a mushroom dish will contain a lethal dose . On the other hand, there is no fatal poisoning by muscimol or ibotenic acid in the literature.
pharmacology
Muscimol is a structural analog of gamma-aminobutyric acid (GABA), and as such a high-affinity , competitive , orthosteric agonist (. E. Ligand on the GABA - binding site ) on GABA A - and partial agonist at GABA A-Rho receptors. Contrary to the original expectation, muscimol does not act as an indiscriminate universal agonist on the multitude of GABA A receptor types. At extrasynaptic GABA A receptors, it shows a superagonistic property with a GABA-related maximum potency of 120 to 140% , which is explained by the lower tendency of muscimol to trigger the desensitization of these receptors. G-protein-coupled GABA B receptors are activated with low affinity . Muscimol is not a substrate for GABA transaminase . As a result, Muscimol activates the inhibitory (central dampening) system of the brain.
Muscimol is bound via salt bridges and hydrogen bonds in the extracellular binding cavity between the subunits α1 - and β2 + of the GABA A ion channel, namely via the amino acid residues Arg 66, Thr 129, Thr202 on the one hand and Glu 155 on the other, with additional concerted binding via a water molecule with the backbone - carbonyl groups of Ser 156 and Tyr157 is possible. Cation – Pi bonds result from the ionized amine function of the ligand with the aromatics Tyr 205 and Phe 200 on the receptor side .
When exploring the structure-activity relationships at GABA A receptors, among the structurally more closely related derivatives, only ( S ) -4,5-dihydromuscimol was found to be somewhat higher in affinity.
Muscimol also leads to an increase in the concentration of serotonin in the synaptic cleft of the nerve cells of the central nervous system.
chemistry
Various approaches exist for preparative synthesis. It is possible starting from γ-chloroacetoacetate, which can be obtained by chlorination of acetoacetic ester or diketene . The keto function of γ-chloroacetoacetate is protected with orthoformate to form the ketal . With hydroxylamine , the ester is converted into hydroxamic acid under gentle conditions . The ketal is deprotected with hydrogen chloride-saturated acetic acid and the ring closure to 3-hydroxy-5-chloromethyl isoxazole is carried out in situ . This intermediate product is aminated by boiling in ammoniacal solution with exchange of the chlorine nucleofug, and so finally the title product is obtained.
Individual evidence
- ↑ a b c d Entry on Muscimol in the GESTIS substance database of the IFA , accessed on February 10, 2017(JavaScript required) .
- ^ A b G. A. Johnston: Muscimol as an ionotropic GABA receptor agonist. In: Neurochemical research. Volume 39, Number 10, October 2014, pp. 1942-1947, doi : 10.1007 / s11064-014-1245-y , PMID 24473816 .
- ↑ a b Entry on Muscimol in the ChemIDplus database of the United States National Library of Medicine (NLM) .
- ↑ GF Müller, CH Eugster: [Muscimol, a Pharmacodynamically Active Substance From Amanita Muscaria]. In: Helvetica chimica acta. Volume 48, June 1965, pp. 910-926, doi : 10.1002 / hlca.19650480427 , PMID 14321963 .
- ↑ a b P. Pevarello, M. Varasi: An Improved Synthesis of Muscimol . In: Synthetic Communications . 22, No. 13, 1992, p. 1939. doi : 10.1080 / 00397919208021324 . References there.
- ↑ a b A.R. Gagneux, F. Häfliger, CH Eugster, R. Good: Synthesis of pantherine (agarin) . In: Tetrahedron Letters . 6, No. 25, 1965, p. 2077. doi : 10.1016 / S0040-4039 (00) 90157-6 .
- ↑ RM Woodward, L. Polenzani, R. Miledi: Characterization of bicuculline / baclofen -insensitive (rho-like) gamma-aminobutyric acid receptors expressed in Xenopus oocytes. II. Pharmacology of gamma-aminobutyric acidA and gamma-aminobutyric acidB receptor agonists and antagonists. In: Molecular pharmacology. Volume 43, Number 4, April 1993, pp. 609-625, PMID 8386310 .
- ↑ D. Chandra, LM Halonen, AM Linden, C. Procaccini, K. Hellsten, GE Homanics, ER Korpi: Prototypic GABA (A) receptor agonist muscimol acts preferentially through forebrain high-affinity binding sites. In: Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. Volume 35, number 4, March 2010, pp. 999-1007, doi : 10.1038 / npp.2009.203 , PMID 20032968 , PMC 2823376 (free full text).
- ↑ T. Yamauchi, T. Hori, T. Takahashi: Presynaptic inhibition by muscimol through GABAB receptors. In: The European journal of neuroscience. Volume 12, Number 9, September 2000, pp. 3433-3436, PMID 10998126 .
- ^ A b J. G. Petersen, R. Bergmann, P. Krogsgaard-Larsen, T. Balle, B. Frølund: Probing the orthosteric binding site of GABAA receptors with heterocyclic GABA carboxylic acid bioisosteres. In: Neurochemical research. Volume 39, Number 6, June 2014, pp. 1005-1015, doi : 10.1007 / s11064-013-1226-6 , PMID 24362592 (review).
- ^ P. Krogsgaard-Larsen, L. Nielsen, E. Falch, DR Curtis: GABA agonists. Resolution, absolute stereochemistry, and enantioselectivity of (S) - (+) - and (R) - (-) - dihydromuscimol. In: Journal of medicinal chemistry. Volume 28, Number 11, November 1985, pp. 1612-1617, PMID 2999396 .
- ↑ Emsbach: Hazardous substances - Plant protection - Environmental protection , Deutscher Apotheker Verlag, Stuttgart 2008. ISBN 978-3-7692-4309-3 .