Importance and prospects for design of selective muscarinic agonists
Language English Country Czech Republic Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't, Review
PubMed
18481916
DOI
10.33549/physiolres.931449
PII: 1449
Knihovny.cz E-resources
- MeSH
- Acetylcholine metabolism MeSH
- Muscarinic Agonists pharmacology MeSH
- Guanosine Triphosphate metabolism MeSH
- Carbachol pharmacology MeSH
- Humans MeSH
- Brain metabolism MeSH
- Pyridines pharmacology MeSH
- Drug Design * MeSH
- Receptor, Muscarinic M1 agonists metabolism MeSH
- Thiadiazoles pharmacology MeSH
- Protein Binding MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Names of Substances
- Acetylcholine MeSH
- Muscarinic Agonists MeSH
- Guanosine Triphosphate MeSH
- Carbachol MeSH
- Pyridines MeSH
- Receptor, Muscarinic M1 MeSH
- Thiadiazoles MeSH
- xanomeline MeSH Browser
There are five subtypes of muscarinic receptors that serve various important physiological functions in the central nervous system and the periphery. Mental functions like attention, learning, and memory are attributed to the muscarinic M1 subtype. These functions decline during natural aging and an early deficit is typical for Alzheimer s disease. In addition, stimulation of the M1 receptor increases non-amyloidogenic processing of the amyloid precursor protein and thus prevents accumulation of noxious beta-amyloid fragments. The selectivity of classical muscarinic agonists among receptor subtypes is very low due to the highly conserved nature of the orthosteric binding site among receptor subtypes. Herein we summarize some recent studies with the functionally-selective M1 agonist xanomeline that indicate complex pharmacological profile of this drug that includes interactions with and activation of receptor from both orthosteric and ectopic binding sites, and the time-dependent changes of ligand binding and receptor activation. These findings point to potential profitability of exploitation of ectopic ligands in the search for truly selective muscarinic receptor agonists.
References provided by Crossref.org
Novel long-acting antagonists of muscarinic ACh receptors