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.
MeSH terms
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Allosteric Regulation
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Animals
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Benzeneacetamides / chemical synthesis*
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Benzeneacetamides / pharmacokinetics
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Benzeneacetamides / pharmacology
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Benzoxazines / chemical synthesis*
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Benzoxazines / pharmacokinetics
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Benzoxazines / pharmacology
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Brain / metabolism
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Calcium / metabolism
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Cell Line
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Cricetinae
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Cricetulus
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Female
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Hepatocytes / metabolism
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Humans
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In Vitro Techniques
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Male
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Maze Learning / drug effects
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Memory, Short-Term / drug effects
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Mice
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Nootropic Agents / chemical synthesis*
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Nootropic Agents / pharmacokinetics
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Nootropic Agents / pharmacology
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Oxazines / chemical synthesis*
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Oxazines / pharmacokinetics
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Oxazines / pharmacology
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptor, Muscarinic M1 / agonists*
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Structure-Activity Relationship
Substances
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Benzeneacetamides
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Benzoxazines
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N-(1-(3-(3-oxo-2,3-dihydrobenzo(1,4)oxazin-4-yl)propyl)piperidin-4-yl)-2-phenylacetamide
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Nootropic Agents
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Oxazines
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Piperidines
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Receptor, Muscarinic M1
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Calcium