Muscarinic Agonist

Muscarinic agonist
	Drug class
	Skeletal structure formula of muscarine
Class identifiers
ATC code	N07
Biological target	muscarinic acetylcholine receptor
External links
MeSH	D018721

Short description: Activating agent of the muscarinic acetylcholine receptor

A muscarinic agonist^[1] is an agent that activates the activity of the muscarinic acetylcholine receptor. 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 agent xanomeline has been proposed as a potential treatment for schizophrenia.^[5]^[6]

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

Muscarinic versus nicotinic activity

Comparison of cholinergic agonists ^[7]
Substance	Receptor specificity		Hydrolysis by acetylcholinesterase	Comments
Substance	Muscarinic	Nicotinic	Hydrolysis by acetylcholinesterase	Comments
Acetylcholine	+++	+++	+++	Endogenous ligand
Carbachol	++	+++	-	Used in the treatment of glaucoma
Methacholine	+++	+	++	Used to diagnose bronchial hyperreactivity,^[8] 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	++	+^[9]	-	Used in research to induce symptoms 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.

References

↑ 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.
↑ "AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease". J Mol Neurosci 19 (1–2): 145–53. 2002. doi:10.1007/s12031-002-0025-3. PMID 12212772.
↑ "M1 muscarinic agonists: Their potential in treatment and as disease-modifying agents in Alzheimer's disease". Drug Development Research 50 (3–4): 291–297. 2000. doi:10.1002/1098-2299(200007/08)50:3/4<291::aid-ddr12>3.0.co;2-6.
↑ 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. PMID 18625455.
↑ "Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia". Am J Psychiatry 165 (8): 1033–9. July 2008. doi:10.1176/appi.ajp.2008.06091591. PMID 18593778.
↑ "Muscarinic agonists for the treatment of cognition in schizophrenia". CNS Spectrums 13 (1): 985–96. November 2008. doi:10.1017/S1092852900014048. PMID 19037177.
↑ 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.
↑ "Methacholine challenge testing: identifying its diagnostic role, testing, coding, and reimbursement". Chest 131 (6): 1932–5. June 2007. doi:10.1378/chest.06-1385. PMID 17565027. https://journal.chestnet.org/article/S0012-3692(15)37533-4/fulltext.
↑ 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. PMID 10602325.

External links

Muscarinic+Agonists at the US National Library of Medicine Medical Subject Headings (MeSH)

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[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.

[2] "AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease". J Mol Neurosci 19 (1–2): 145–53. 2002. doi:10.1007/s12031-002-0025-3. PMID 12212772.

[3] "M1 muscarinic agonists: Their potential in treatment and as disease-modifying agents in Alzheimer's disease". Drug Development Research 50 (3–4): 291–297. 2000. doi:10.1002/1098-2299(200007/08)50:3/4<291::aid-ddr12>3.0.co;2-6.

[pmid18625455-4] 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. PMID 18625455.

[pmid18593778-5] "Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia". Am J Psychiatry 165 (8): 1033–9. July 2008. doi:10.1176/appi.ajp.2008.06091591. PMID 18593778.

[pmid19037177-6] "Muscarinic agonists for the treatment of cognition in schizophrenia". CNS Spectrums 13 (1): 985–96. November 2008. doi:10.1017/S1092852900014048. PMID 19037177.

[Rang&Dale6thUnless-7] 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.

[pmid17565027-8] "Methacholine challenge testing: identifying its diagnostic role, testing, coding, and reimbursement". Chest 131 (6): 1932–5. June 2007. doi:10.1378/chest.06-1385. PMID 17565027. https://journal.chestnet.org/article/S0012-3692(15)37533-4/fulltext.

[9] 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. PMID 10602325.

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