Muscarine

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Muscarine
Chemical structure of muscarine
Muscarine-3D-balls.png
Identifiers
CAS number 300-54-9 YesY
PubChem 9308
ChemSpider 8949 YesY
ChEMBL CHEMBL12587 YesY
Jmol-3D images Image 1
Properties
Molecular formula C9H20NO2+
Molar mass 174.26 g/mol
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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Infobox references
Amanita muscaria

Muscarine, L-(+)-muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. 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 Boletus, Hygrocybe, Lactarius and Russula. Muscarine is only a trace compound in the fly agaric Amanita muscaria; the pharmacologically more relevant compound from this mushroom is muscimol. The A. muscaria contains 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]

It is a nonselective agonist of the muscarinic acetylcholine receptor.

History[edit]

Muscarine was first isolated from Amanita muscaria in 1869. It was the first parasympathomimetic substance ever studied and causes profound activation of the peripheral parasympathetic nervous system that may end in convulsions and death. Being a quaternary amine, muscarine is less completely absorbed from the gastrointestinal tract than tertiary amines, but it does cross the blood brain barrier.[2] Muscarinic agonists activate muscarinic receptors while nicotinic agonists activate nicotin 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 Jellinek (61) in 1957 with the help of X-ray diffraction analysis. These new findings set into motion research not only on the pharmacology of muscarine, but also on that of muscarine-like substances that are structurally related to acetylcholine.

Structure and reactivity[edit]

‘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.[3]

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

Efficient synthesis of (+)-muscarine[edit]

The next is a very efficient way of synthesis of (+)-muscarine according to the scientists Chan and Li in the Canadian journal of Chemistry in 1992.[4] S-(-)-Ethyl lactate (2)(figure 3) 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).[4]

Figure 3. The scheme of synthesis of (+)-muscarine.

Other Syntheses[edit]

It can be synthesized in various ways from completely different substances,[5][6][7][8][9][10][11][12][13][14] particularly from 2,5-dimethyl-3-carboxymethyl flurane.

Mechanism of action[edit]

Muscarine mimics the action of the neurotransmitter acetylcholine by binding muscarinic acetylcholine receptors. These receptors were named after muscarine. There are 5 different types of muscarinic receptors; M1 - M5, and most tissues express a mixture of subtypes. The M2 and M3 subtypes mediate muscarinic responses at peripheral autonomic tissues. M1 and M4 subtypes are more abundant in brain and autonomic ganglia. M1, M3 and M5 interact with Gq proteins to stimulate phosphoinositide hydrolysis and the release of intracellular calcium. M2 and M4 receptors 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.[15]

Metabolism[edit]

A paucity of research exists on the metabolism of muscarine in the human body, suggesting this compound is not metabolized. 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 toxicity. Muscarine is readily soluble in water. The most likely way to leave the blood is via renal clearance and it will eventually leave the body in urine.[16]

Drug[edit]

Muscarinic agonists are used as drugs in treating glaucoma, postoperative ileus, congenital megacolon, urinary retention and xerostomia. Muscarine is contraindicated in patients with diseases that make them susceptible to parasympathetic stimulation, patients who have asthma or COPD or patients who have peptic ulcer disease. Also patients 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. The applications of muscarine to the treatment of disease are yet in their infancy. The physiological effects indicate the direction of the remedial applications. As muscarine stimulates so powerfully the muscular fiber of the intestine, and the secretions of the pancreas, liver, and intestinal mucous membrane, it ought to be very serviceable in cases of constipation with torpor of the organs concerned in digestion. When constipation is due to paresis of the muscular layer of the bowel and to deficient secretion, this remedy will likely relieve it. Muscarine can also be used in combination with other remedies for the treatment of intestinal torpor and deficient secretion. Muscarine is of doubtful propriety, if not positively contra-indicated, in renal afflictions characterized by deficiency in the excretion. On the other hand, it ought to be of signal service in diabetes insipidus and in saccharine diabetes. It has been used successfully to arrest the secretion of milk.[17]

Efficacy[edit]

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 actions 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.[18]

Toxicology[edit]

Muscarine poisoning is characterized by miosis, blurred vision, increased salivation, excessive sweating, lacrimation, bronchial secretions, bronchoconstriction, bradycardia, abdominal cramping, increased gastic 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.[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 pharynx. Then salivation, lacrimation, and diffuse perspiration set in, combined with miosis, disturbed 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 diagnosis and treatment with atropine.[19]

Antidote[edit]

The specific antidote is atropine. Atropine is also an alkaloid and inhibits acetylcholine and thus muscarine by binding to muscarinic receptors. Other muscarinic antagonists are scopolamine and pirenzepine. 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 parasympatic nerves.

See also[edit]

References[edit]

  1. ^ a b Lurie, Y; Wasser, SP; Taha, M; Shehade, H; Nijim, J; Hoffmann, Y; Basis, F; Vardi, M; Lavon, O; Suaed, S; Bisharat, B; Bentur, Y (July 2009). "Mushroom poisoning from species of genus Inocybe (fiber head mushroom): a case series with exact species identification.". Clinical toxicology (Philadelphia, Pa.) 47 (6): 562–5. doi:10.1080/15563650903008448. PMID 19566380. 
  2. ^ Pappano Achilles J, "Chapter 7. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs" (Chapter). Katzung BG: Basic & Clinical Pharmacology, 11e
  3. ^ Frydenvang, K.; Jensen, B. (15 May 1993). "Structures of muscarine picrate and muscarine tetraphenylborate". Acta Crystallographica Section C Crystal Structure Communications 49 (5): 985–990. doi:10.1107/S0108270192012198. 
  4. ^ a b Chan, T. H.; Li, C. J. (November 1992). "A concise synthesis of (+)-muscarine". Canadian Journal of Chemistry 70 (11): 2726–2729. doi:10.1139/v92-346. 
  5. ^ Kögl, F.; Salemink, C. A.; Schouten, H.; Jellinek, F. (2010). "Über Muscarin. III". Recueil des Travaux Chimiques des Pays-Bas 76 (2): 109. doi:10.1002/recl.19570760204.  edit
  6. ^ Kögl, F.; Cox, H. C.; Salemink, C. A. (1957). "Über Muscarin". Experientia 13 (4): 137. doi:10.1007/BF02158130.  edit
  7. ^ Corrodi, H.; Hardegger, E.; Kögl, F.; Zeller, P. (1957). "Synthese von Stereoisomeren des Muscarins". Experientia 13 (4): 138. doi:10.1007/BF02158131.  edit
  8. ^ Cox, H. C.; Hardegger, E.; Kögl, F.; Liechti, P.; Lohse, F.; Salemink, C. A. (1958). "Über Muscarin. 9. Mitteilung. Über die Synthese von racemischem Muscarin, seine Spaltung in die Antipoden und die Herstellung von (−)-Muscarin aus D-Glucosamin". Helvetica Chimica Acta 41: 229. doi:10.1002/hlca.660410129.  edit
  9. ^ Matsumoto, T.; Ichihara, A.; Ito, N. (1969). "A simple, stereospecific synthesis of dl-muscarine and dl-allomuscarine". Tetrahedron 25 (24): 5889. doi:10.1016/S0040-4020(01)83096-9.  edit
  10. ^ Still, W. C.; Schneider, J. A. (1980). "Chelation-controlled synthesis of (.+-.)-muscarine". The Journal of Organic Chemistry 45 (16): 3375. doi:10.1021/jo01304a056.  edit
  11. ^ Whiting, J.; Au-Young, Y. -K.; Belleau, B. (1972). "A Convenient Synthesis ofL(+)-Muscarine". Canadian Journal of Chemistry 50 (20): 3322. doi:10.1139/v72-532.  edit
  12. ^ Mubarak, A. M.; Brown, D. M. (1980). "A simple, stereospecific synthesis of (+)-muscarine". Tetrahedron Letters 21 (25): 2453. doi:10.1016/S0040-4039(00)93174-5.  edit
  13. ^ Mubarak, A. M.; Brown, D. M. (1982). "A stereospecific synthesis of (+)-muscarine". Journal of the Chemical Society, Perkin Transactions 1: 809. doi:10.1039/P19820000809.  edit
  14. ^ Pochet, S.; Huynh Dinh Tam (1982). "Stereospecific synthesis of muscarines and allomuscarines in D- and L-series". The Journal of Organic Chemistry 47 (2): 193. doi:10.1021/jo00341a003.  edit
  15. ^ Theodore M. Brody, Joseph Larner, Kenneth P. Minneman, ed. (1998). "Chapter 9". Human pharmacology : molecular to clinical (3rd ed. ed.). St. Louis, Mo.: Mosby. ISBN 0815124562. 
  16. ^ Roberts Bartholow, “A practical treatise on materia medica and therapeutics”, 1908, ISBN 978-1-143-46767-7,
  17. ^ Roberts Bartholow; "A Practical Treatise On Materia Medica And Therapeutics"; 1908, Appleton And Company
  18. ^ Fraser, PJ (March 1957). "Pharmacological actions of pure muscarine chloride". Br J Pharmacol Chemother. 12 (1): 47–52. doi:10.1111/j.1476-5381.1957.tb01361.x. PMC 1509643. PMID 13413151. 
  19. ^ Peter G. Waser; Chemistry and pharmacology of muscarine, muscarone and some related compounds; Pharmacology Department, University of Zurich, Switzerland 1961

External links[edit]