View source for Muscarinic agonist

{{Short description|Activating agent of the muscarinic acetylcholine receptor}}
{{Infobox drug class
| Name = Muscarinic agonist
| Image = Muscarine.svg
| ImageClass = skin-invert-image
| Synonyms = Muscarinic acetylcholine receptor agonist; Muscarinic receptor agonist; Muscarinic; Muscarinic drug; Muscarinic agent; Muscarinic medication; mACh agonist; mAChR agonist
| Use = 
| Caption = [[Skeletal formula|Skeletal structure formula]] of [[muscarine]]
| Biological_target = [[muscarinic acetylcholine receptor]]
| ATC_prefix = N07
| MeshID = D018721
}}

A '''muscarinic acetylcholine receptor agonist''', also simply known as a '''muscarinic agonist''' or as a '''muscarinic agent''', is an agent that activates the activity of the [[muscarinic acetylcholine receptor]].<ref>{{Cite journal |last1=Broadley |first1=Kenneth J. |last2=Kelly |first2=David R. |date=2001-02-28 |title=Muscarinic Receptor Agonists and Antagonists |journal=Molecules |volume=6 |issue=3 |pages=142–193 |doi=10.3390/60300142 |issn=1420-3049 |pmc=6236374 |doi-access=free }}</ref> The muscarinic receptor has different subtypes, labelled M1-M5, allowing for further differentiation.

==Clinical significance==

=== M1 ===

M1-type muscarinic [[acetylcholine]] receptors  play a role in [[cognition|cognitive]] processing.  In [[Alzheimer disease]] (AD), [[amyloid]] formation may decrease the ability of these receptors to transmit signals, leading to decreased cholinergic activity. As these receptors themselves appear relatively unchanged in the disease process, they have become a potential therapeutic target  when trying to improve cognitive function in patients with AD.<ref>{{cite journal | vauthors = Fisher A, Brandeis R, Bar-Ner RH, Kliger-Spatz M, Natan N, Sonego H, Marcovitch I, Pittel Z | year = 2002 | title = AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease | journal = [[J Mol Neurosci]] | volume = 19 | issue = 1–2| pages = 145–53 | pmid = 12212772 | doi = 10.1007/s12031-002-0025-3 | s2cid = 21773972 }}</ref><ref>{{cite journal | vauthors = Fisher A | year = 2000 | title = M1 muscarinic agonists: Their potential in treatment and as disease-modifying agents in Alzheimer's disease | journal = Drug Development Research | volume = 50 | issue = 3–4 | pages = 291–297 | doi = 10.1002/1098-2299(200007/08)50:3/4<291::aid-ddr12>3.0.co;2-6 | s2cid = 85100519 | doi-access = free }}</ref><ref name="pmid18625455">{{cite journal |author=Fisher A |title=Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer's disease |journal=[[Neurotherapeutics]] |volume=5 |issue=3 |pages=433–42 |date=July 2008 |pmid=18625455 |doi=10.1016/j.nurt.2008.05.002 |pmc=5084245 }}</ref>

A number of muscarinic agonists have been developed and are under investigation to treat AD. These agents show promise as they are [[neurotrophin|neurotrophic]], decrease amyloid depositions, and improve damage due to [[oxidative stress]]. [[Tau protein|Tau]]-phosphorylation is decreased and   cholinergic function enhanced.  Notably several agents of the AF series of muscarinic agonists have become the focus of such research:. '''AF102B, AF150(S), AF267B'''. In animal models that are mimicking the damage of AD, these agents appear promising.

The dual M1, M4 agonist [[xanomeline]] has been proposed as a potential treatment for [[schizophrenia]].<ref name="pmid18593778">{{cite journal  |vauthors=Shekhar A, Potter WZ, Lightfoot J, etal |title=Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia |journal=Am J Psychiatry |volume= 165|issue= 8|pages= 1033–9|date=July 2008 |pmid=18593778 |doi=10.1176/appi.ajp.2008.06091591 |s2cid=24308125 }}</ref><ref name="pmid19037177">{{cite journal |vauthors=Sellin AK, Shad M, Tamminga C |title=Muscarinic agonists for the treatment of cognition in schizophrenia |journal=CNS Spectrums |volume=13 |issue=1 |pages=985–96 |date=November 2008 |pmid=19037177 |doi= 10.1017/S1092852900014048|s2cid=12642499 }}</ref> [[Xanomeline/trospium chloride]] was approved in the US in 2024.<ref>{{cite press release | title=U.S. Food and Drug Administration Approves Bristol Myers Squibb's Cobenfy (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults | publisher=Bristol Myers Squibb | via=Business Wire | date=27 September 2024 | url=https://www.businesswire.com/news/home/20240925382351/en/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibb%E2%80%99s-COBENFY%E2%84%A2-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults | access-date=27 September 2024}}</ref> Based on preclinical pharmacological and genetic studies, M1 predominantly modulates cognitive symptom domains and modestly regulates psychosis symptom domains.<ref name=pmid35758639/> 

=== M3 ===

In the form of [[pilocarpine]], muscarinic receptor agonists have been used medically for a short time.
* M3 agonists
** '''[[Aceclidine]]''', for glaucoma
** '''[[Arecoline]]''', an alkaloid present in the [[Betel nut]]
** '''[[Pilocarpine]]''' is a drug that acts as a muscarinic receptor agonist that is used to treat [[glaucoma]]
** '''[[Cevimeline]]''' (AF102B) (Evoxac®) is a muscarinic agonist that is  a [[Food and Drug Administration]] (FDA)-[[approved drug]] and used for the management of [[dry mouth]] in [[Sjögren's syndrome]]

=== M4 ===
Xanomeline exerts its action partially through the M4 receptor. Based on preclinical pharmacological and genetic studies, M4 receptors appear to modulate both [[psychosis]] and cognitive symptom domains.<ref>{{cite journal | vauthors = Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA | title = Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice | journal = European Journal of Pharmacology | volume = 603 | issue = 1–3 | pages = 147–149 | date = January 2009 | pmid = 19111716 | doi = 10.1016/j.ejphar.2008.12.020 }}</ref><ref name=pmid35758639>{{cite journal | vauthors = Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC | title = Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia | journal = The American Journal of Psychiatry | volume = 179 | issue = 9 | pages = 611–627 | date = September 2022 | pmid = 35758639 | doi = 10.1176/appi.ajp.21101083 | s2cid = 250070840 }}</ref>

==Muscarinic versus nicotinic activity==
{| class="wikitable"
!colspan=5| Comparison of cholinergic agonists <ref name=Rang&Dale6thUnless>Unless else specified in boxes, then reference is: Table 10-3 in: {{cite book |author1=Rod Flower |author2=Humphrey P. Rang |author3=Maureen M. Dale |author4=Ritter, James M. |title=Rang & Dale's pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2007 |isbn=978-0-443-06911-6 }}</ref>
|-
! rowspan="2" |Substance
! colspan="2" |Receptor specificity
! rowspan="2" |Hydrolysis by [[acetylcholinesterase]]
! rowspan="2" |Comments
|-
!Muscarinic
!Nicotinic
|-
| [[Acetylcholine]] || +++ || +++ || +++ || Endogenous ligand
|-
| [[Carbachol]] || ++ || +++ || - || Used in the treatment of [[glaucoma]]
|-
| [[Methacholine]] || +++ || + || ++ || Used to diagnose [[bronchial hyperreactivity]],<ref name="pmid17565027">{{cite journal|vauthors=Birnbaum S, Barreiro TJ|date=June 2007|title=Methacholine challenge testing: identifying its diagnostic role, testing, coding, and reimbursement|url=https://journal.chestnet.org/article/S0012-3692(15)37533-4/fulltext|journal=Chest|volume=131|issue=6|pages=1932–5|doi=10.1378/chest.06-1385|pmid=17565027}}</ref> a hallmark of [[asthma]] and [[COPD]].
|-
| [[Bethanechol]] || +++ || - || - || Used in bladder and gastrointestinal hypotonia.
|-
| [[Muscarine]] || +++ || - || - || Natural [[alkaloid]] found in certain mushrooms.
Cause of one form of mushroom poisoning
|-
| [[Nicotine]] || - || +++ || - || Natural alkaloid found in the [[tobacco plant]].
|-
| [[Pilocarpine]] || ++ || - || - || Used in glaucoma.
|-
| [[Oxotremorine]] || ++ ||+<ref>{{Cite journal|title = Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists|journal = British Journal of Pharmacology|date = 1999-12-01|issn = 0007-1188|pmc = 1571784|pmid = 10602325|pages = 1467–1476|volume = 128|issue = 7|doi = 10.1038/sj.bjp.0702941|first1 = Gustav|last1 = Akk|first2 = Anthony|last2 = Auerbach}}</ref>|| - || Used in research to induce
symptoms of [[Parkinson's disease]].
|}

== Muscarinic acetylcholine receptor subtypes ==
{{expand section|date=April 2019}}
{{main|Muscarinic acetylcholine receptor#Receptor isoforms}}
The targets for muscarinic agonists are the muscarinic receptors: [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]], [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]], [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]], [[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]] and [[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]]. These receptors are [[GPCRs]] coupled to either [[Gi subunit|Gi]] or [[Gq subunits]].

== See also ==
* [[Muscarine]]
* [[Muscarinic acetylcholine receptor]]
* [[Muscarinic antagonist]]
* [[Nicotinic acetylcholine receptor]]
* [[Nicotinic agonist]]
* [[Nicotinic antagonist]]

== References ==
{{reflist|30em}}

==External links==
* {{MeshName|Muscarinic+Agonists}}

{{Pharmacomodulation}}
{{Acetylcholine receptor modulators}}

[[Category:Muscarinic agonists| ]]