Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylac etamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
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Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B
Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylac etamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
J Med Chem. 2010 Sep 9;53(17):6386-97. doi: 10.1021/jm100697g.
- PubMed ID
- 20684563 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Acetylcholine Muscarinic acetylcholine receptor M1 EC 50 (nM) 1.1 N/A N/A Details Acetylcholine Muscarinic acetylcholine receptor M2 EC 50 (nM) 220 N/A N/A Details Acetylcholine Muscarinic acetylcholine receptor M3 EC 50 (nM) 3.2 N/A N/A Details Acetylcholine Muscarinic acetylcholine receptor M4 EC 50 (nM) 10 N/A N/A Details