Amuscarinic acetylcholine receptor agonist, also known as amuscarinic agonist or as amuscarinic agent, is an agent that activates themuscarinic acetylcholine receptor.[1] The muscarinic receptor has different subtypes, labelled M1-M5, allowing further differentiation.
M1-type muscarinicacetylcholine receptors play a role incognitive processing. InAlzheimer 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 areneurotrophic, decrease amyloid depositions, and improve damage due tooxidative 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 agonistxanomeline has been proposed as a potential treatment forschizophrenia.[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]
Xanomeline exerts its action partially through the M4 receptor. Based on preclinical pharmacological and genetic studies, M4 receptors appear to modulate bothpsychosis and cognitive symptom domains.[9][8]
^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.PMID12212772.S2CID21773972.
^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.PMID18593778.S2CID24308125.
^abPaul 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.PMID35758639.S2CID250070840.
^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.PMID19111716.
^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.ISBN978-0-443-06911-6.
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