Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential
| Autor: | Christoffer Bundgaard, Niels Plath, Krestian Larsen, Anette Graven Sams, Benny Bang-Andersen, Gitte Mikkelsen, Morten Hentzer, Claus Tornby Christoffersen |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
Male medicine.drug_class Stereochemistry Allosteric regulation Benzeneacetamides In Vitro Techniques Cell Line Rats Sprague-Dawley Mice Radioligand Assay Structure-Activity Relationship Cricetulus Allosteric Regulation Piperidines In vivo Cricetinae Drug Discovery Muscarinic acetylcholine receptor Oxazines medicine Animals Humans Receptor Maze Learning Ion channel Nootropic Agents Chemistry Receptor Muscarinic M1 Brain Muscarinic acetylcholine receptor M1 Benzoxazines Rats Memory Short-Term Hepatocytes Molecular Medicine Calcium Female Selectivity |
| Zdroj: | Journal of medicinal chemistry. 53(17) |
| ISSN: | 1520-4804 |
| Popis: | The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17. |
| Databáze: | OpenAIRE |
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