Muscarine

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Muscarine
Chemical structure of muscarine
Names
IUPAC name
2,5-Anhydro-1,4,6-trideoxy-6-(trimethylazaniumyl)-D-ribo-hexitol
Systematic IUPAC name
1-[(2S,4R,5S)-4-Hydroxy-5-methyloxolan-2-yl]-N,N,N-trimethylmethanaminium
Other names
L-(+)-muscarine, muscarin, (2S,4R,5S)-(4-hydroxy-5-methyl-tetrahydrofuran-2-ylmethyl)-trimethyl-ammonium
Identifiers
3D model (
JSmol
)
ChEMBL
ChemSpider
ECHA InfoCard
 100.005.541 Edit this at Wikidata
IUPHAR/BPS
UNII
  • InChI=1S/C9H20NO2/c1-7-9(11)5-8(12-7)6-10(2,3)4/h7-9,11H,5-6H2,1-4H3/q+1/t7-,8-,9+/m0/s1 checkY
    Key: UQOFGTXDASPNLL-XHNCKOQMSA-N checkY
  • InChI=1/C9H20NO2/c1-7-9(11)5-8(12-7)6-10(2,3)4/h7-9,11H,5-6H2,1-4H3/q+1/t7-,8-,9+/m0/s1
    Key: UQOFGTXDASPNLL-XHNCKOQMBJ
  • O[C@@H]1C[C@H](O[C@H]1C)C[N+](C)(C)C
Properties
C9H20NO2+
Molar mass 174.26 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Amanita muscaria

Muscarine, L-(+)-muscarine, or muscarin is a

Z-drug-like alkaloid muscimol. A. muscaria fruitbodies contain a variable dose of muscarine, usually around 0.0003% fresh weight. This is very low and toxicity symptoms occur very rarely. Inocybe and Clitocybe contain muscarine concentrations up to 1.6%.[1]

Muscarine is a selective agonist of the muscarinic acetylcholine receptors.

History

The name muscarine derives from that of

Latin
musca for fly because the mushroom was often used to attract and catch flies, hence its common name, "fly agaric".

Muscarine was the first

quaternary ammonium salt, muscarine is less completely absorbed from the gastrointestinal tract than tertiary amines, and it does not cross the blood–brain barrier.[3]
Muscarinic agonists activate muscarinic receptors while nicotinic agonists activate nicotine receptors. Both are direct-acting cholinomimetics; they produce their effects by binding to and activating cholinergic receptors. Final proof of the structure was given by Franz Jellinek and colleagues in 1957 with the help of
X-ray diffraction analysis;[4] Jellinek further described the three-dimensional structure of the molecule using muscarine chloride.[5] These new findings set into motion research on the pharmacology of muscarine and muscarine-like substances that are structurally related to acetylcholine
.

Structure and reactivity

Muscarine mimics the function of the natural neurotransmitter acetylcholine in the muscarinic part of the cholinergic nervous system, despite the less flexible structure due to the five-membered ring in the molecular skeleton. With the exception of the double bonded oxygen, all of the acetylcholine structure is present in the right bottom side of muscarine (see Figure 3 below for comparison of both structures).[6]

There are two mirror forms of muscarine, named: 2S-muscarine and 2R-muscarine.

  • Figure 1. The structural formula of 2S-muscarine.
    Figure 1. The structural formula of 2S-muscarine.
  • Figure 2. The structural formula of 2R-muscarine.
    Figure 2. The structural formula of 2R-muscarine.
  • Figure 3. Acetylcholine for comparison.
    Figure 3. Acetylcholine for comparison.

Efficient synthesis of (+)-muscarine

The scheme below represents a very efficient way of the synthesis of (+)-muscarine according to the scientists Chan and Li in the Canadian journal of Chemistry in 1992.[7] S-(−)-Ethyl lactate (2)(Figure 4) is converted into the 2,6-dichlorobenzyl ether (3). Diisobutylaluminium hydride (DIBAL) reduction of the 2,6-dichlorobenzyl ether gives the aldehyde (4). Treatment of the crude aldehyde with allyl bromide and zinc powder in water with NH4Cl as catalyst resulted in an anti:syn mixture of 5a and 5b. Treatment of 5a with iodine in CH3CN at 0 °C gives the cyclized product 6a. Finally treatment of 6a with excess trimethylamine in ethanol gave (+)-muscarine (2S,4R,5S). A similar reaction sequence with 5b gave (+)-epimuscarine (7).[7]

Figure 4. Scheme of the synthesis of (+)-muscarine.

Other Syntheses

It can be synthesized in various ways from completely different substances,[8][9][10][11][12][13][14][15][16][17] particularly from 2,5-dimethyl-3-carboxymethyl flurane.

Pharmacology

Pharmacodynamics

Muscarine mimics the action of the

M5
. Most tissues express a mixture of subtypes. The M2 and M3 subtypes mediate muscarinic responses at
autonomic ganglia
. The odd numbered receptors, M1, M3 and M5, interact with
Gi
proteins to inhibit adenylyl cyclase, which results in a decrease of intracellular concentration of cyclic adenosine monophosphate (cAMP). Most agonists for muscarine receptors are not selective for subtypes.[18]

Muscarinic receptors also signal via other pathways, for instance via G beta-gamma complex modulation of potassium channels. This allows muscarine to modulate cellular excitability via the membrane potential.

Metabolism

A paucity of research exists on the metabolism of muscarine in the human body, suggesting this compound is not metabolized by humans. Though there has been extensive research in the field of acetylcholine metabolism by acetylcholinesterase, muscarine is not metabolized by this enzyme, partly explaining the compound's potential toxicity. Muscarine is readily soluble in water. The most likely way for muscarine to leave the blood is via renal clearance; it will eventually leave the body in urine.[19]

Medical uses

Muscarinic agonists are used as drugs in treating

urinary tract
are not prescribed muscarine because it will aggravate the obstruction, causing pressure to build up that may lead to perforation.

Efficacy

As muscarine works on the muscarinic acetylcholine receptor, the best comparison can be made with acetylcholine, which normally works on this receptor. Pure muscarine compared to pure acetylcholine is stated in most cases to be more potent, its action is always slower but longer lasting than acetylcholine. A possible explanation for this long-lasting behavior might be that muscarine does not get hydrolyzed by acetylcholinesterase in the synaptic cleft.[20]

Toxicology

Muscarine poisoning is characterized by

convulsions and hypothermia
.
circulatory failure with cardiac arrest.[1]
The symptoms of intoxication with mushrooms rich in muscarine, especially Inocybe, are very typical: The symptoms start early, after one-quarter to two hours, with headache, nausea, vomiting, and constriction of the
circulatory shock. Death after 8 to 9 hours has been reported in about 5% of the cases, but can be avoided completely by prompt administration of IV or IM anticholinergic drugs.[21]

Antidote

Antimuscarinics such as atropine can be used as an antidote
to muscarine. Atropine is, like muscarine, an alkaloid but unlike muscarine is an antagonist of the muscarinic receptors. Hence, it inhibits the effects of acetylcholine. Muscarinic antagonists dilate the pupil and relax the ciliary muscle, are used in treatment of inflammatory uveitis and is associated with glaucoma. They are also used to treat urinary incontinence and diseases characterized by bowel hypermotility such as irritable bowel syndrome. Muscarinic antagonists are often called
parasympatholytics
because they have the same effect as agents that block postganglionic parasympathetic nerves.

References

  1. ^
    S2CID 205902282
    .
  2. ^ Schmiedeberg, O.; Koppe, R. (1869). Das Muscarin, das giftige Alkaloid des Fliegenpilzes (Agaricus muscarius L.), seine Darstellung, chemischen Eigenschaften, physiologischen Wirkungen, toxicologische Bedeutung und sein Verhältniss zur Pilzvergiftung im allgemeinen [Muscarine, the poisonous alkaloid of the fly agaric (Agaricus muscarius L.), its preparation, chemical properties, physiological effects, toxicological importance, and its relation to mushroom poisoning in general]. Leipzig: Verlag von F.C.W. Vogel.
  3. ^ Pappano Achilles J, "Chapter 7. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs" (Chapter). Katzung BG: Basic & Clinical Pharmacology, 11e Archived 2009-09-10 at the Wayback Machine
  4. doi:10.1002/recl.19570760204
    .
  5. doi:10.1107/S0365110X57000845
    .
  6. doi:10.1107/S0108270192012198
    .
  7. ^
    doi:10.1139/v92-346
    .
  8. doi:10.1002/recl.19570760204
    .
  9. S2CID 38142806
    .
  10. S2CID 28914321
    .
  11. doi:10.1002/hlca.660410129
    .
  12. doi:10.1016/S0040-4020(01)83096-9
    .
  13. doi:10.1021/jo01304a056
    .
  14. doi:10.1139/v72-532
    .
  15. doi:10.1016/S0040-4039(00)93174-5
    .
  16. doi:10.1039/P19820000809
    .
  17. doi:10.1021/jo00341a003
    .
  18. ISBN 0815124562
    .
  19. ISBN 978-1-143-46767-7
    ,
  20. PMID 13413151
    .
  21. ^ Peter G. Waser; Chemistry and pharmacology of muscarine, muscarone and some related compounds; Pharmacology Department, University of Zurich, Switzerland 1961

External links

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