Muscarinic agonist explained

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.

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.

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.^{[8] [9]}

Muscarinic versus nicotinic activity

Comparison of cholinergic agonists [10]
Substance	Receptor specificity		Hydrolysis by acetylcholinesterase	Comments
	Muscarinic	Nicotinic
	+++	+++	+++	Endogenous ligand
	++	+++	-	Used in the treatment of glaucoma
	+++	+	++	Used to diagnose bronchial hyperreactivity,[11] a hallmark of asthma and COPD.
	+++	-	-	Used in bladder and gastrointestinal hypotonia.
	+++	-	-	Natural alkaloid found in certain mushrooms.Cause of one form of mushroom poisoning
	-	+++	-	Natural alkaloid found in the tobacco plant.
	++	-	-	Used in glaucoma.
	++	+[12]	-	Used in research to inducesymptoms of Parkinson's disease.

Muscarinic acetylcholine receptor subtypes

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

Notes and References

1. Broadley . Kenneth J. . Kelly . David R. . 2001-02-28 . Muscarinic Receptor Agonists and Antagonists . Molecules . 6 . 3 . 142–193 . 10.3390/60300142 . 1420-3049 . 6236374 . free .
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 . . 19 . 1–2. 145–53 . 12212772 . 10.1007/s12031-002-0025-3 . 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 . 10.1002/1098-2299(200007/08)50:3/4<291::aid-ddr12>3.0.co;2-6 . 85100519 . free .
4. Fisher A . Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer's disease . . 5 . 3 . 433–42 . July 2008 . 18625455 . 10.1016/j.nurt.2008.05.002 . 5084245 .
5. Shekhar A, Potter WZ, Lightfoot J, etal . Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia . Am J Psychiatry . 165. 8. 1033–9. July 2008 . 18593778 . 10.1176/appi.ajp.2008.06091591 . 24308125 .
6. Sellin AK, Shad M, Tamminga C . Muscarinic agonists for the treatment of cognition in schizophrenia . CNS Spectrums . 13 . 1 . 985–96 . November 2008 . 19037177 . 10.1017/S1092852900014048. 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 . Bristol Myers Squibb . Business Wire . 27 September 2024 . 27 September 2024.
8. Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA . 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 . January 2009 . 19111716 . 10.1016/j.ejphar.2008.12.020 .
9. Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC . Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia . The American Journal of Psychiatry . 179 . 9 . 611–627 . September 2022 . 35758639 . 10.1176/appi.ajp.21101083 . 250070840 .
10. Unless else specified in boxes, then reference is: Table 10-3 in: Book: Rod Flower . Humphrey P. Rang . Maureen M. Dale . Ritter, James M. . Rang & Dale's pharmacology . Churchill Livingstone . Edinburgh . 2007 . 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. 10.1378/chest.06-1385. 17565027.
12. Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists. British Journal of Pharmacology. 1999-12-01. 0007-1188. 1571784. 10602325. 1467–1476. 128. 7. 10.1038/sj.bjp.0702941. Gustav. Akk. Anthony. Auerbach.