Muscarinic agonist

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.^[1] The muscarinic receptor has different subtypes, labelled M1-M5, allowing for further differentiation.

Muscarinic agonist
Drug class
Skeletal structure formula of muscarine
Class identifiers
Synonyms	Muscarinic acetylcholine receptor agonist; Muscarinic receptor agonist; Muscarinic; Muscarinic drug; Muscarinic agent; Muscarinic medication; mACh agonist; mAChR agonist
ATC code	N07
Biological target	muscarinic acetylcholine receptor
External links
MeSH	D018721
Legal status
In Wikidata

Clinical significance

M1

M1-type muscarinic acetylcholine receptors play a role in 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.^[2][3][4]

A number of muscarinic agonists have been developed and are under investigation to treat AD. These agents show promise as they are neurotrophic, decrease amyloid depositions, and improve damage due to oxidative stress. 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.^[5][6] Xanomeline/trospium chloride was approved in the US in 2024.^[7] Based on preclinical pharmacological and genetic studies, M1 predominantly modulates cognitive symptom domains and modestly regulates psychosis symptom domains.^[8]

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.^[9][8]

Muscarinic versus nicotinic activity

Comparison of cholinergic agonists [10]
Substance	Receptor specificity		Hydrolysis by acetylcholinesterase	Comments
	Muscarinic	Nicotinic
Acetylcholine	+++	+++	+++	Endogenous ligand
Carbachol	++	+++	-	Used in the treatment of glaucoma
Methacholine	+++	+	++	Used to diagnose bronchial hyperreactivity,[11] 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	++	+[12]	-	Used in research to induce symptoms of Parkinson's disease.

Muscarinic acetylcholine receptor subtypes

Main article: Muscarinic acetylcholine receptor § Receptor isoforms

The targets for muscarinic agonists are the muscarinic receptors: M₁, M₂, M₃, M₄ and M₅. These receptors are GPCRs coupled to either Gi or Gq subunits.

See also

• Muscarine
• Muscarinic acetylcholine receptor
• Muscarinic antagonist
• Nicotinic acetylcholine receptor
• Nicotinic agonist
• Nicotinic antagonist

References

1. Broadley, Kenneth J.; Kelly, David R. (2001-02-28). "Muscarinic Receptor Agonists and Antagonists". Molecules. 6 (3): 142–193. doi:10.3390/60300142. ISSN 1420-3049. PMC 6236374.
2. Fisher A, Brandeis R, Bar-Ner RH, Kliger-Spatz M, Natan N, Sonego H, Marcovitch I, Pittel Z (2002). "AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease". J Mol Neurosci. 19 (1–2): 145–53. doi:10.1007/s12031-002-0025-3. PMID 12212772. S2CID 21773972.
3. Fisher A (2000). "M1 muscarinic agonists: Their potential in treatment and as disease-modifying agents in Alzheimer's disease". Drug Development Research. 50 (3–4): 291–297. doi:10.1002/1098-2299(200007/08)50:3/4<291::aid-ddr12>3.0.co;2-6. S2CID 85100519.
4. Fisher A (July 2008). "Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer's disease". Neurotherapeutics. 5 (3): 433–42. doi:10.1016/j.nurt.2008.05.002. PMC 5084245. PMID 18625455.
5. Shekhar A, Potter WZ, Lightfoot J, et al. (July 2008). "Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia". Am J Psychiatry. 165 (8): 1033–9. doi:10.1176/appi.ajp.2008.06091591. PMID 18593778. S2CID 24308125.
6. Sellin AK, Shad M, Tamminga C (November 2008). "Muscarinic agonists for the treatment of cognition in schizophrenia". CNS Spectrums. 13 (1): 985–96. doi:10.1017/S1092852900014048. PMID 19037177. S2CID 12642499.
7. "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" (Press release). Bristol Myers Squibb. 27 September 2024. Retrieved 27 September 2024 – via Business Wire.
8. Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC (September 2022). "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". The American Journal of Psychiatry. 179 (9): 611–627. doi:10.1176/appi.ajp.21101083. PMID 35758639. S2CID 250070840.
9. Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA (January 2009). "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". European Journal of Pharmacology. 603 (1–3): 147–149. doi:10.1016/j.ejphar.2008.12.020. PMID 19111716.
10. Unless else specified in boxes, then reference is: Table 10-3 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-06911-6.
11. Birnbaum S, Barreiro TJ (June 2007). "Methacholine challenge testing: identifying its diagnostic role, testing, coding, and reimbursement". Chest. 131 (6): 1932–5. doi:10.1378/chest.06-1385. PMID 17565027.
12. Akk, Gustav; Auerbach, Anthony (1999-12-01). "Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists". British Journal of Pharmacology. 128 (7): 1467–1476. doi:10.1038/sj.bjp.0702941. ISSN 0007-1188. PMC 1571784. PMID 10602325.

External links

• Muscarinic+Agonists at the U.S. National Library of Medicine Medical Subject Headings (MeSH)