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4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor

Mistry, Shailesh N.; Jörg, Manuela; Lim, Herman; Vinh, Natalie B.; Sexton, Patrick M.; Capuano, Ben; Christopoulos, Arthur; Lane, J. Robert; Scammells, Peter J.

Authors

Manuela Jörg

Herman Lim

Natalie B. Vinh

Patrick M. Sexton

Ben Capuano

Arthur Christopoulos

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor

Peter J. Scammells



Abstract

Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimer’s and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a diverse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization.

Journal Article Type Article
Publication Date Jan 14, 2016
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 59
Issue 1
Pages 388-409
APA6 Citation Mistry, S. N., Jörg, M., Lim, H., Vinh, N. B., Sexton, P. M., Capuano, B., …Scammells, P. J. (2016). 4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor. Journal of Medicinal Chemistry, 59(1), 388-409. https://doi.org/10.1021/acs.jmedchem.5b01562
DOI https://doi.org/10.1021/acs.jmedchem.5b01562
Publisher URL http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01562
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi...21/acs.jmedchem.5b01562

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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