View source for Muscarine

{{Distinguish|Mescaline}}{{chembox
| Verifiedimages = changed
| Watchedfields = changed
| verifiedrevid = 436370910
|   Name = Muscarine
|   ImageFile_Ref = {{chemboximage|correct|??}}
| ImageFile = Muscarine.svg
| ImageClass = skin-invert-image
| ImageSize = 200px
|   ImageFile2 = Muscarine-3D-balls.png
|   ImageSize2 = 220px
|   ImageName = Chemical structure of muscarine
|   IUPACName = 2,5-Anhydro-1,4,6-trideoxy-6-(trimethylazaniumyl)-<small>D</small>-''ribo''-hexitol
|   SystematicName = 1-[(2''S'',4''R'',5''S'')-4-Hydroxy-5-methyloxolan-2-yl]-''N'',''N'',''N''-trimethylmethanaminium
|   OtherNames =<small>L</small>-(+)-muscarine, muscarin, (2''S'',4''R'',5''S'')-(4-hydroxy-5-methyl-tetrahydrofuran-2-ylmethyl)-trimethyl-ammonium
| Section1 = {{Chembox Identifiers
| IUPHAR_ligand = 3996
|   ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 8949
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 12587
| PubChem = 9308
| 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
| InChIKey = UQOFGTXDASPNLL-XHNCKOQMBJ
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = UQOFGTXDASPNLL-XHNCKOQMSA-N
| CASNo_Ref = {{cascite|correct|??}}
| CASNo = 300-54-9
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 7T101UWZ5W
|   SMILES = O[C@@H]1C[C@H](O[C@H]1C)C[N+](C)(C)C
}}
| Section2 = {{Chembox Properties
|   Formula = C<sub>9</sub>H<sub>20</sub>NO<sub>2</sub><sup>+</sup>
|   MolarMass = 174.26 g/mol
  }}
}}[[File:Amanita muscaria.jpg|thumb|''Amanita muscaria'']]

'''Muscarine''', '''<small>L</small>-(+)-muscarine''', or '''muscarin''' is a [[Secondary metabolite|natural product]] found in certain [[mushroom]]s, particularly in ''[[Inocybe]]'' and ''[[Clitocybe]]'' species, such as the deadly ''[[Clitocybe dealbata|C.&nbsp;dealbata]]''. Mushrooms in the genera ''[[Entoloma]]'' and ''[[Mycena]]'' have also been found to contain levels of muscarine which can be dangerous if ingested. Muscarine has been found in harmless trace amounts in the genera ''[[Boletus]]'', ''[[Hygrocybe]]'', ''[[Lactarius (fungus)|Lactarius]]'' and ''[[Russula]]''. Trace concentrations of muscarine are also found in ''[[Amanita muscaria]]'', though the pharmacologically more relevant compound from this mushroom is the [[gabaergic]] drug [[muscimol]]. ''A.&nbsp;muscaria'' [[basidiocarp|fruitbodies]] contain a variable dose of muscarine, usually around 0.0003% of total fresh weight. This is very low and toxicity symptoms occur very rarely. Highly toxic ''Inocybe'' and ''Clitocybe'' species contain muscarine concentrations up to 1.6%.<ref name="pmid19566380">{{cite journal|last=Lurie|first=Y |author2=Wasser, SP |author3=Taha, M |author4=Shehade, H |author5=Nijim, J |author6=Hoffmann, Y |author7=Basis, F |author8=Vardi, M |author9=Lavon, O |author10=Suaed, S |author11=Bisharat, B |author12=Bentur, Y|title=Mushroom poisoning from species of genus ''Inocybe'' (fiber head mushroom): a case series with exact species identification |journal=Clinical Toxicology|date=July 2009|volume=47|issue=6|pages=562–5|doi=10.1080/15563650903008448|pmid=19566380|s2cid=205902282 }}</ref>

Muscarine is a selective [[agonist]] of the [[muscarinic acetylcholine receptor]]s.

==History==
The name ''muscarine'' derives from that of ''[[Amanita muscaria]]'', from which it was first isolated, by German chemists [[Oswald Schmiedeberg]] and Richard Koppe at the [[University of Tartu]], who reported their findings in 1869.<ref name="Schmiedeberg 1869">{{cite book |author1=Schmiedeberg, O. |author2=Koppe, R. |title=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 |trans-title=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 |year=1869 |location=Leipzig |publisher=Verlag von F.C.W. Vogel |url=https://books.google.com/books?id=_FZVYpYGrUkC&pg=PP3}}</ref> The mushroom's [[binomial nomenclature|specific name]] in turn comes from the [[Latin language|Latin]] {{Lang|la|musca}} for fly because the mushroom was often used to attract and catch flies, hence its common name, "fly agaric".

Muscarine was the first [[parasympathomimetic]] substance ever studied. It causes profound activation of the [[Peripheral nervous system|peripheral]] [[parasympathetic nervous system]] that may end in circulatory collapse and death. Being a [[quaternary ammonium salt]], muscarine is less completely absorbed from the [[gastrointestinal tract]] than tertiary amines, and it does not cross the [[blood–brain barrier]].<ref>[http://www.accessmedicine.com/content.aspx?aID=4511248 Pappano Achilles J, "Chapter 7. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs" (Chapter). Katzung BG: Basic & Clinical Pharmacology, 11e] {{webarchive|url=https://web.archive.org/web/20090910090807/http://www.accessmedicine.com/content.aspx?aID=4511248 |date=2009-09-10 }}</ref>
Muscarinic agonists activate muscarinic receptors while nicotinic agonists activate nicotine receptors. Both are direct-acting [[cholinomimetic]]s; they produce their effects by binding to and activating [[cholinergic receptor]]s.
Final proof of the structure was given by Franz Jellinek and colleagues in 1957 with the help of [[X-ray diffraction]] analysis;<ref name="Kögl 1957">{{cite journal |author1=Kögl, F. |author2=Salemink, C.A. |author3=Schouten, H. |author4=Jellinek, F. |title=Über Muscarin. III |journal=Recueil des Travaux Chimiques des Pays-Bas |year=1957 |volume=76 |issue=2 |pages=109–127 |language=German |doi=10.1002/recl.19570760204}}</ref> Jellinek further described the three-dimensional structure of the molecule using muscarine chloride.<ref name="Jellinek 1957">{{cite journal |author=Jellinek, F. |title=The structure of muscarine |journal=Acta Crystallographica |year=1957 |volume=10 |issue=4 |pages=277–280 |doi=10.1107/S0365110X57000845|bibcode=1957AcCry..10..277J }}</ref> 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).<ref>{{cite journal|last=Frydenvang|first=K.|author2=Jensen, B.|title=Structures of muscarine picrate and muscarine tetraphenylborate|journal=Acta Crystallographica Section C|date=15 May 1993|volume=49|issue=5|pages=985–990|doi=10.1107/S0108270192012198|bibcode=1993AcCrC..49..985F |doi-access=free}}</ref>

There are two mirror forms of muscarine, named: 2S-muscarine and 2R-muscarine.
<div class="skin-invert-image"><gallery>
Image:2S-muscarine.png|Figure 1. The structural formula of 2S-muscarine.
Image:2R-Muscarin.png|Figure 2. The structural formula of 2R-muscarine.
image:Acetylcholine.svg|Figure 3. Acetylcholine for comparison.
</gallery></div>

===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.<ref name="Chan1992">{{cite journal|last=Chan|first=T. H.|author2=Li, C. J.|title=A concise synthesis of (+)-muscarine|journal=Canadian Journal of Chemistry|date=November 1992|volume=70|issue=11|pages=2726–2729|doi=10.1139/v92-346|doi-access=free|bibcode=1992CaJCh..70.2726C }}</ref>
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 NH<sub>4</sub>Cl as catalyst resulted in an anti:syn mixture of 5a and 5b. Treatment of 5a with iodine in CH<sub>3</sub>CN at 0&nbsp;°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).<ref name="Chan1992" />
[[File:synthese (+)-muscarin.gif|class=skin-invert-image|thumb|none|upright=2.0|Figure 4. Scheme of the synthesis of (+)-muscarine.]]

===Other Syntheses===
It can be synthesized in various ways from completely different substances,<ref>{{Cite journal | doi = 10.1002/recl.19570760204| title = Über Muscarin. III| journal = Recueil des Travaux Chimiques des Pays-Bas| volume = 76| issue = 2| pages = 109| year = 2010| last1 = Kögl | first1 = F.| last2 = Salemink | first2 = C. A.| last3 = Schouten | first3 = H.| last4 = Jellinek | first4 = F.}}</ref><ref>{{Cite journal | doi = 10.1007/BF02158130| title = Über Muscarin| journal = Experientia| volume = 13| issue = 4| pages = 137–8| year = 1957| last1 = Kögl | first1 = F.| last2 = Cox | first2 = H. C.| last3 = Salemink | first3 = C. A.| pmid = 13447893| s2cid = 38142806}}</ref><ref>{{Cite journal | doi = 10.1007/BF02158131| title = Synthese von Stereoisomeren des Muscarins| journal = Experientia| volume = 13| issue = 4| pages = 138–9| year = 1957| last1 = Corrodi | first1 = H.| last2 = Hardegger | first2 = E.| last3 = Kögl | first3 = F.| last4 = Zeller | first4 = P.| pmid = 13447894| s2cid = 28914321}}</ref><ref>{{Cite journal | doi = 10.1002/hlca.660410129| title = Über Muscarin. 9. Mitteilung. Über die Synthese von racemischem Muscarin, seine Spaltung in die Antipoden und die Herstellung von (−)-Muscarin aus D-Glucosamin| journal = Helvetica Chimica Acta| volume = 41| pages = 229–234| year = 1958| last1 = Cox | first1 = H. C.| last2 = Hardegger | first2 = E.| last3 = Kögl | first3 = F.| last4 = Liechti | first4 = P.| last5 = Lohse | first5 = F.| last6 = Salemink | first6 = C. A.}}</ref><ref>{{Cite journal | doi = 10.1016/S0040-4020(01)83096-9| title = A simple, stereospecific synthesis of dl-muscarine and dl-allomuscarine| journal = Tetrahedron| volume = 25| issue = 24| pages = 5889| year = 1969| last1 = Matsumoto | first1 = T.| last2 = Ichihara | first2 = A.| last3 = Ito | first3 = N.}}</ref><ref>{{Cite journal | doi = 10.1021/jo01304a056| title = Chelation-controlled synthesis of (.+-.)-muscarine| journal = The Journal of Organic Chemistry| volume = 45| issue = 16| pages = 3375| year = 1980| last1 = Still | first1 = W. C. | last2 = Schneider | first2 = J. A. }}</ref><ref>{{Cite journal | doi = 10.1139/v72-532| title = A Convenient Synthesis ofL(+)-Muscarine| journal = Canadian Journal of Chemistry| volume = 50| issue = 20| pages = 3322| year = 1972| last1 = Whiting | first1 = J.| last2 = Au-Young | first2 = Y. -K. | last3 = Belleau | first3 = B.| doi-access = free}}</ref><ref>{{Cite journal | doi = 10.1016/S0040-4039(00)93174-5| title = A simple, stereospecific synthesis of (+)-muscarine| journal = Tetrahedron Letters| volume = 21| issue = 25| pages = 2453| year = 1980| last1 = Mubarak | first1 = A. M. | last2 = Brown | first2 = D. M. }}</ref><ref>{{Cite journal | doi = 10.1039/P19820000809| title = A stereospecific synthesis of (+)-muscarine| journal = Journal of the Chemical Society, Perkin Transactions 1| pages = 809| year = 1982| last1 = Mubarak | first1 = A. M. | last2 = Brown | first2 = D. M. }}</ref><ref>{{Cite journal | doi = 10.1021/jo00341a003| title = Stereospecific synthesis of muscarines and allomuscarines in D- and L-series| journal = The Journal of Organic Chemistry| volume = 47| issue = 2| pages = 193| year = 1982| last1 = Pochet | first1 = S. | last2 = Huynh Dinh Tam}}</ref> particularly from 2,5-dimethyl-3-carboxymethyl flurane.

== Pharmacology ==
===Pharmacodynamics===
Muscarine mimics the action of the [[neurotransmitter]] [[acetylcholine]] by [[agonist|agonising]] [[muscarinic acetylcholine receptor]]s. These receptors were named after muscarine, to differentiate them from the other [[acetylcholine]] receptors ([[nicotinic receptor]]s), which are comparatively unresponsive to muscarine. There are five different types of muscarinic receptors: [[M1 receptor|M<sub>1</sub>]], [[M2 receptor|M<sub>2</sub>]], [[M3 receptor|M<sub>3</sub>]], [[M4 receptor|M<sub>4</sub>]] and [[M5 receptor|M<sub>5</sub>]]. Most tissues express a mixture of subtypes.

The M<sub>2</sub> and M<sub>3</sub> subtypes mediate muscarinic responses at [[peripheral nervous system|peripheral autonomic tissues]]. M<sub>1</sub> and M<sub>4</sub> subtypes are more abundant in [[brain]] and [[autonomic ganglia]].

The odd numbered receptors, M<sub>1</sub>, M<sub>3</sub> and M<sub>5</sub>, interact with [[Gq protein|G<sub>q</sub>]] proteins to stimulate phosphoinositide hydrolysis and the release of intracellular calcium. Conversely, the even numbered receptors, M<sub>2</sub> and M<sub>4</sub>, interact with [[Gi protein|G<sub>i</sub>]] 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.<ref>{{cite book|editor1=Theodore M. Brody |editor2=Joseph Larner |editor3=Kenneth P. Minneman |title=Human Pharmacology: Molecular to Clinical|year=1998|publisher=Mosby|location=St. Louis, Mo.|isbn=0815124562|edition=3rd|chapter=Chapter 9}}</ref>

Muscarinic receptors also signal via other pathways, for instance via [[G beta-gamma complex]] modulation of [[potassium channel]]s. 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.<ref>Roberts Bartholow, “A practical treatise on materia medica and therapeutics”, 1908, {{ISBN|978-1-143-46767-7}},</ref>

== Medical uses ==
{{More medical citations needed|section|date=November 2019}}

Muscarinic agonists are used as drugs in treating [[glaucoma]], postoperative [[ileus]], congenital [[megacolon]], [[urinary retention]] and [[xerostomia]]. Muscarine is [[contraindicated]] in people with diseases that make them susceptible to parasympathetic stimulation, people who have [[asthma]] or [[COPD]], or people who have [[peptic ulcer]] disease. Also people with an obstruction in the [[gastrointestinal]] or [[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.<ref name="pmid13413151">{{cite journal|last=Fraser|first=PJ|title=Pharmacological actions of pure muscarine chloride|journal=Br J Pharmacol Chemother|date=March 1957|volume=12|issue=1|pages=47–52|doi=10.1111/j.1476-5381.1957.tb01361.x|pmid=13413151|pmc=1509643}}</ref>

== Toxicology ==
Muscarine poisoning is characterized by [[miosis]], blurred vision, increased [[salivation]], excessive [[sweating]], [[lacrimation]], bronchial secretions, bronchoconstriction, [[bradycardia]], abdominal cramping, increased gastric acid secretion, diarrhea and [[polyuria]]. If muscarine reaches the brain it can cause [[tremor]], [[convulsions]] and [[hypothermia]].
[[Cardiac ventricles]] contain [[muscarinic receptors]] that mediate a decrease in the force of contractions leading to a lower blood pressure. If muscarine is administered intravenously, muscarine can trigger acute [[circulatory failure]] with [[cardiac arrest]].<ref name="pmid19566380" />

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 [[pharynx]]. Then salivation, lacrimation, and diffuse perspiration set in, combined with miosis, disturbed [[accommodation (eye)|accommodation]], and reduced vision. Gastric and small bowel [[colic]] leads to diarrhea, and there is a painful urge for urination. [[Bronchoconstriction]] leads to asthmatic attacks and severe [[dyspnea]], and bradycardia combined with marked [[hypotension]] and [[vasodilation]] results in [[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.<ref>Peter G. Waser; Chemistry and pharmacology of muscarine, muscarone and some related compounds; Pharmacology Department, University of Zurich, Switzerland 1961</ref>

== Antidote ==
[[Antimuscarinic]]s 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 [[mydriasis|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 ==
{{Reflist|28em}}

== External links ==
* [https://emedicine.medscape.com/article/167398-overview Treatment of muscarine poisoning]
* [https://www.erowid.org/plants/amanitas/ Psychoactive ''Amanitas'' on Erowid]

{{Poisonous Amanitas}}
{{Muscarinic acetylcholine receptor modulators}}
{{Toxins}}

[[Category:Alkaloids]]
[[Category:M1 receptor agonists]]
[[Category:M2 receptor agonists]]
[[Category:M3 receptor agonists]]
[[Category:M4 receptor agonists]]
[[Category:M5 receptor agonists]]
[[Category:Mycotoxins]]
[[Category:Quaternary ammonium compounds]]