Muscarinic agonist
| Muscarinic agonist | |
|---|---|
| Drug class | |
 | |
| Class identifiers | |
| ATC code | N07 |
| Biological target | muscarinic acetylcholine receptor |
| External links | |
| MeSH | D018721 |
| Legal status | |
| In Wikidata | |
Amuscarinic agonist[1]is an agent that activates the activity of themuscarinic acetylcholine receptor.The muscarinic receptor has different subtypes, labelled M1-M5, allowing for further differentiation.
Clinical significance
[edit]M1
[edit]M1-type muscarinicacetylcholinereceptors play a role incognitiveprocessing. InAlzheimer disease(AD),amyloidformation 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 agonistxanomelinehas been proposed as a potential treatment forschizophrenia.[5][6]Xanomeline/trospium chloridewas 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
[edit]In the form ofpilocarpine,muscarinic receptor agonists have been used medically for a short time.
- M3 agonists
- Aceclidine,for glaucoma
- Arecoline,an alkaloid present in theBetel nut
- Pilocarpineis a drug that acts as a muscarinic receptor agonist that is used to treatglaucoma
- Cevimeline(AF102B) (Evoxac®) is a muscarinic agonist that is aFood and Drug Administration(FDA)-approved drugand used for the management ofdry mouthinSjögren's syndrome
M4
[edit]Xanomeline exerts its action partially through the M4 receptor. Based on preclinical pharmacological and genetic studies, M4 receptors appear to modulate bothpsychosisand cognitive symptom domains.[9][8]
Muscarinic versus nicotinic activity
[edit]| Comparison of cholinergic agonists[10] | ||||
|---|---|---|---|---|
| Substance | Receptor specificity | Hydrolysis byacetylcholinesterase | Comments | |
| Muscarinic | Nicotinic | |||
| Acetylcholine | +++ | +++ | +++ | Endogenous ligand |
| Carbachol | ++ | +++ | - | Used in the treatment ofglaucoma |
| Methacholine | +++ | + | ++ | Used to diagnosebronchial hyperreactivity,[11]a hallmark ofasthmaandCOPD. |
| Bethanechol | +++ | - | - | Used in bladder and gastrointestinal hypotonia. |
| Muscarine | +++ | - | - | Naturalalkaloidfound in certain mushrooms.
Cause of one form of mushroom poisoning |
| Nicotine | - | +++ | - | Natural alkaloid found in thetobacco plant. |
| Pilocarpine | ++ | - | - | Used in glaucoma. |
| Oxotremorine | ++ | +[12] | - | Used in research to induce
symptoms ofParkinson's disease. |
Muscarinic acetylcholine receptor subtypes
[edit]![[icon]](/translate/en.wikipedia.org?u=https%3A%2F%2Fen.wikipedia.org%2Fwiki%2FFile%3AWiki_letter_w_cropped.svg&t=hv){kind=small} | This sectionneeds expansion.You can help byadding to it.(April 2019) |
The targets for muscarinic agonists are the muscarinic receptors:M1,M2,M3,M4andM5.These receptors areGPCRscoupled to eitherGiorGq subunits.
See also
[edit]- Muscarine
- Muscarinic acetylcholine receptor
- Muscarinic antagonist
- Nicotinic acetylcholine receptor
- Nicotinic agonist
- Nicotinic antagonist
References
[edit]- ^Broadley, Kenneth J.; Kelly, David R. (2001-02-28)."Muscarinic Receptor Agonists and Antagonists".Molecules.6(3): 142–193.doi:10.3390/60300142.ISSN1420-3049.PMC6236374.
- ^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.
- ^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.S2CID85100519.
- ^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.PMC5084245.PMID18625455.
- ^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.
- ^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.PMID19037177.S2CID12642499.
- ^"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.Retrieved27 September2024– via Business Wire.
- ^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.
- ^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.PMID17565027.
- ^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.ISSN0007-1188.PMC1571784.PMID10602325.
External links
[edit]- Muscarinic+Agonistsat the U.S. National Library of MedicineMedical Subject Headings(MeSH)