Muscarine
Encyclopedia
Muscarine, L--muscarine, or muscarin is a natural product
found in certain mushroom
s, 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%.
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.
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.
There are two mirror forms of muscarin, named: 2S-muscarine and 2R-muscarine.
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).
acetylcholine
by binding muscarinic acetylcholine receptor
s. 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.
, 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.
, 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 probably 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 affections 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.
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 then acetylcholine. A possible explanation for this long lasting behavior might be that muscarine doesn’t get hydrolyzed by acetylcholinesterase in the synaptic cleft.
, 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.
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.
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 it's 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.
Secondary metabolite
Secondary metabolites are organic compounds that are not directly involved in the normal growth, development, or reproduction of an organism. Unlike primary metabolites, absence of secondary metabolities does not result in immediate death, but rather in long-term impairment of the organism's...
found in certain mushroom
Mushroom
A mushroom is the fleshy, spore-bearing fruiting body of a fungus, typically produced above ground on soil or on its food source. The standard for the name "mushroom" is the cultivated white button mushroom, Agaricus bisporus; hence the word "mushroom" is most often applied to those fungi that...
s, particularly in Inocybe
Inocybe
Inocybe is a large, complex genus of mushrooms. Members of Inocybe are mycorrhizal, and some evidence shows that the high degree of speciation in the genus is due to adaptation to different trees and perhaps even local environments.-Description:...
and Clitocybe
Clitocybe
Hundreds of species of mushrooms compose the fungus genus Clitocybe. They are characterized by white, off-white, buff, cream, pink, or light-yellow spores, gills running down the stem, and pale white to brown or lilac coloration. They are primarily saprotrophic, decomposing forest ground litter...
species, such as the deadly C. dealbata
Clitocybe dealbata
Clitocybe dealbata, also known as the ivory funnel, is a small white funnel-shaped toadstool widely found in lawns, meadows and other grassy areas in Europe and North America. Also known as the sweating mushroom, it derives this name from the symptoms of poisoning...
. Mushrooms in the genera Entoloma
Entoloma
Entoloma is a large genus of terrestrial pink-gilled mushrooms, with about 1000 species. They have a drab appearance, pink gills which are attached to the stem, a smooth thick cap, and angular spores. Most entolomas are saprobic...
and Mycena
Mycena
Mycena is a large genus of small saprotrophic mushrooms that are rarely more than a few centimeters in width. They are characterized by a white spore print, a small conical or bell-shaped cap, and a thin fragile stem. Most are gray or brown, but a few species have brighter colors. Most have a...
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
Boletus
Boletus is a genus of mushroom, comprising over 100 species. The genus Boletus was originally broadly defined and described by Elias Magnus Fries in 1821, essentially containing all fungi with pores...
, Hygrocybe
Hygrocybe
Hygrocybe is a genus of agarics in the family Hygrophoraceae. Called "waxcaps" in English , basidiocarps are often brightly coloured and have waxy to slimy caps, white spores, and smooth, ringless stems...
, Lactarius
Lactarius
Lactarius is a genus of mushroom-producing fungi. The genus, collectively known commonly as milk-caps, are characterized by the fact that they exude a milky fluid if cut or damaged...
and Russula
Russula
Around 750 worldwide species of mycorrhizal mushrooms compose the genus Russula. They are typically common, fairly large, and brightly colored - making them one of the most recognizable genera among mycologists and mushroom collectors...
. Muscarine is only a trace compound in the fly agaric Amanita muscaria
Amanita muscaria
Amanita muscaria, commonly known as the fly agaric or fly amanita , is a poisonous and psychoactive basidiomycete fungus, one of many in the genus Amanita...
; the pharmacologically more relevant compound from this mushroom is muscimol
Muscimol
Muscimol is the major psychoactive alkaloid present in many mushrooms of the Amanita genus. Unlike psilocin , which is a serotonergic psychedelic and agonist for the 5-HT2A receptor set, muscimol is a potent, selective agonist for the GABAA receptor set and is a deliriant as a opposed...
. 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%.
History
Muscarine was first isolated from Amanita muscariaAmanita muscaria
Amanita muscaria, commonly known as the fly agaric or fly amanita , is a poisonous and psychoactive basidiomycete fungus, one of many in the genus Amanita...
in 1869. It was the first parasympathomimetic substance ever studied and causes profound activation of the peripheral
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
parasympathetic nervous system
Parasympathetic nervous system
The parasympathetic nervous system is one of the two main divisions of the autonomic nervous system . The ANS is responsible for regulation of internal organs and glands, which occurs unconsciously...
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.
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
‘Muscarine mimics the function of the natural neurotransmitter acetylcholine in the muscarinic part of the cholinergic nervous system.’ Despite of the less flexible structure due to the five-membered ring in the molecular skeleton.There are two mirror forms of muscarin, named: 2S-muscarine and 2R-muscarine.
Efficient synthesis of (+)-muscarine
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.S-(-)-Ethyl lactate (2)(figure 3) is converted into the 2,6-dichlorobenzyl ether (3). Diisobutylaluminium hydride
Diisobutylaluminium hydride
Diisobutylaluminium hydride, DIBAL, DIBAL-H or DIBAH, is a reducing agent with the formula 2, where i-Bu represents isobutyl...
(DIBAL) reduction of the 2,6-dichlorobenzyl ether gives the aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
(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).
Mechanism of action
Muscarine mimics the action of the neurotransmitterNeurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
by binding muscarinic acetylcholine receptor
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s. 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.
Metabolism
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 acetylcholinesteraseAcetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
, 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.
Drug
Muscarinic agonists are used as drugs in treating glaucomaGlaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, postoperative ileus
Ileus
Ileus is a disruption of the normal propulsive ability of the gastrointestinal tract.Ileus is commonly defined simply as bowel obstruction. However, authoritative sources define it as decreased motor activity of the GI tract due to non-mechanical causes...
, congenital megacolon, urinary retention
Urinary retention
Urinary retention, also known as ischuria, is a lack of ability to urinate. It is a common complication of benign prostatic hyperplasia , although it can also be caused by nerve dysfunction, constipation, infection, or medications...
and Xerostomia
Xerostomia
Xerostomia is the medical term for the subjective complaint of dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties, cottonmouth, drooth, or doughmouth. Several diseases, treatments, and medications can cause xerostomia. It can also be exacerbated by smoking or...
.
Muscarine is contraindicated in patients with diseases that make them susceptible to parasympathetic stimulation, patients who have asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
or COPD or patients who have peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
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 probably 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 affections 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.
Efficacy
As muscarine works on the muscarinic acetylcholine receptorMuscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
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 then acetylcholine. A possible explanation for this long lasting behavior might be that muscarine doesn’t get hydrolyzed by acetylcholinesterase in the synaptic cleft.
Toxicology
Muscarine poisoning is characterized by miosisMiosis
Miosis is the constriction of the pupil of the eye to two millimeters or less...
, blurred vision, increased salivation, excessive sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, lacrimation, bronchial secretions, bronchoconstriction, bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
, abdominal cramping, increased gastic acid secretion, diarrhea and polyuria
Polyuria
Polyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...
. If muscarine reaches the brain it can cause tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, convulsions and hypothermia
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
.
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.
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.
Antidote
The specific antidoteAntidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
is atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
. Atropine is also an alkaloid and inhibits acetylcholine and thus muscarine by binding to muscarinic receptors. Other muscarinic antagonists are scopolamine
Scopolamine
Scopolamine, also known as levo-duboisine, and hyoscine, is a tropane alkaloid drug with muscarinic antagonist effects. It is among the secondary metabolites of plants from Solanaceae family of plants, such as henbane, jimson weed and Angel's Trumpets , and corkwood...
and pirenzepine
Pirenzepine
Pirenzepine is used in the treatment of peptic ulcers, as it reduces gastric acid secretion and reduces muscle spasm. It is in a class of drugs known as muscarinic receptor antagonists - acetylcholine being the neurotransmitter of the parasympathetic nervous system which initiates the...
.
Muscarinic antagonists dilate the pupil and relax the ciliary muscle, are used in treatment of inflammatory uveitis and it's associated with glaucoma. They are also used to treat urinary incontinence and diseases characterized by bowel hypermotility such as irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
.
Muscarinic antagonists are often called parasympatholytics because they have the same effect as agents that block postganglionic parasympatic nerves.