Muscarinic agonist

A muscarinic agonist 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.

Muscarine

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.[1][2][3]

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.[4][5]

M3

In the form of pilocarpine, muscarinic receptor agonists have been used medically for a short time.

Muscarinic versus nicotinic activity
Comparison of cholinergic agonists [6]
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,[7] 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+++[8]-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.

See also

References
  1. 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.
  2. Fisher A (2000). "M1 muscarinic agonists: Their potential in treatment and as disease-modifying agents in Alzheimer's disease". Drug Development Research. 50: 291–297. doi:10.1002/1098-2299(200007/08)50:3/4<291::aid-ddr12>3.0.co;2-6. Archived from the original on 2012-12-10.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
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