4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor
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...
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| Format: | Article |
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American Chemical Society
2015
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| Online Access: | https://eprints.nottingham.ac.uk/31240/ |
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| author | Mistry, Shailesh N. Jörg, Manuela Lim, Herman Vinh, Natalie B. Sexton, Patrick M. Capuano, Ben Christopoulos, Arthur Lane, J. Robert Scammells, Peter J. |
| author_facet | Mistry, Shailesh N. Jörg, Manuela Lim, Herman Vinh, Natalie B. Sexton, Patrick M. Capuano, Ben Christopoulos, Arthur Lane, J. Robert Scammells, Peter J. |
| author_sort | Mistry, Shailesh N. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:11:44Z |
| format | Article |
| id | nottingham-31240 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:11:44Z |
| publishDate | 2015 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-312402020-05-04T17:20:57Z https://eprints.nottingham.ac.uk/31240/ 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. 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. American Chemical Society 2015-12-01 Article PeerReviewed Mistry, Shailesh N., Jörg, Manuela, Lim, Herman, Vinh, Natalie B., Sexton, Patrick M., Capuano, Ben, Christopoulos, Arthur, Lane, J. Robert and Scammells, Peter J. (2015) 4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor. Journal of Medicinal Chemistry . ISSN 1520-4804 http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01562 doi:10.1021/acs.jmedchem.5b01562 doi:10.1021/acs.jmedchem.5b01562 |
| spellingShingle | Mistry, Shailesh N. Jörg, Manuela Lim, Herman Vinh, Natalie B. Sexton, Patrick M. Capuano, Ben Christopoulos, Arthur Lane, J. Robert Scammells, Peter J. 4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor |
| title | 4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor |
| title_full | 4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor |
| title_fullStr | 4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor |
| title_full_unstemmed | 4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor |
| title_short | 4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor |
| title_sort | 4-phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the m1 muscarinic acetylcholine receptor |
| url | https://eprints.nottingham.ac.uk/31240/ https://eprints.nottingham.ac.uk/31240/ https://eprints.nottingham.ac.uk/31240/ |