Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor

An iterative analogue library synthesis strategy rapidly developed comprehensive SAR data for a novel series of M4 positive allosteric modulators (PAMs). This effort identified key moieties that improved microsomal stability and physiochemical properties. Moreover, this series displayed an order of...

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Bibliographic Details
Published in:ChemMedChem 2009-10, Vol.4 (10), p.1600-1607
Main Authors: Kennedy, J. Phillip, Bridges, Thomas M., Gentry, Patrick R., Brogan, John T., Kane, Alexander S., Jones, Carrie K., Brady, Ashley E., Shirey, Jana K., Conn, P. Jeffrey, Lindsley, Craig W.
Format: Article
Language:English
Subjects:
allosteric
muscarinic
potentiators
receptors
schizophrenia
structure–activity relationships
Online Access:Get full text
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Summary:An iterative analogue library synthesis strategy rapidly developed comprehensive SAR data for a novel series of M4 positive allosteric modulators (PAMs). This effort identified key moieties that improved microsomal stability and physiochemical properties. Moreover, this series displayed an order of magnitude greater potency for human versus rat M4, providing compounds with EC50 values in the 100 nM range.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.200900231