Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor
Established therapy in Alzheimer’s disease involves potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortex and hippocampus. Adverse effects, due to indiscriminate activation of other muscarinic receptor subtypes,...
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| Format: | Article |
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American Chemical Society
2013
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| Online Access: | https://eprints.nottingham.ac.uk/30413/ |
| _version_ | 1848793980425207808 |
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| author | Mistry, Shailesh N. Valant, Celine Sexton, Patrick M. Capuano, Ben Christopoulos, Arthur Scammells, Peter J. |
| author_facet | Mistry, Shailesh N. Valant, Celine Sexton, Patrick M. Capuano, Ben Christopoulos, Arthur Scammells, Peter J. |
| author_sort | Mistry, Shailesh N. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Established therapy in Alzheimer’s disease involves potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortex and hippocampus. Adverse effects, due to indiscriminate activation of other muscarinic receptor subtypes, are common. M1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution, being exquisitely M1-selective over other muscarinic subtypes. A common difficulty with allosteric ligands is interpreting SAR, based on composite potency values derived in the presence of fixed concentration of agonist. In reality these values encompass multiple pharmacological parameters, each potentially and differentially sensitive to structural modification of the ligand. We report novel BQCA analogues which appear to augment ligand affinity for the receptor (pKB), intrinsic efficacy (τB), and both binding (α) and functional (β) cooperativity with acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators will provide insight into their mode of action. |
| first_indexed | 2025-11-14T19:08:55Z |
| format | Article |
| id | nottingham-30413 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:08:55Z |
| publishDate | 2013 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-304132020-05-04T16:37:20Z https://eprints.nottingham.ac.uk/30413/ Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor Mistry, Shailesh N. Valant, Celine Sexton, Patrick M. Capuano, Ben Christopoulos, Arthur Scammells, Peter J. Established therapy in Alzheimer’s disease involves potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortex and hippocampus. Adverse effects, due to indiscriminate activation of other muscarinic receptor subtypes, are common. M1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution, being exquisitely M1-selective over other muscarinic subtypes. A common difficulty with allosteric ligands is interpreting SAR, based on composite potency values derived in the presence of fixed concentration of agonist. In reality these values encompass multiple pharmacological parameters, each potentially and differentially sensitive to structural modification of the ligand. We report novel BQCA analogues which appear to augment ligand affinity for the receptor (pKB), intrinsic efficacy (τB), and both binding (α) and functional (β) cooperativity with acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators will provide insight into their mode of action. American Chemical Society 2013-06-17 Article PeerReviewed Mistry, Shailesh N., Valant, Celine, Sexton, Patrick M., Capuano, Ben, Christopoulos, Arthur and Scammells, Peter J. (2013) Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor. Journal of Medicinal Chemistry, 56 (12). pp. 5151-5172. ISSN 0022-2623 http://pubs.acs.org/doi/abs/10.1021/jm400540b doi:10.1021/jm400540b doi:10.1021/jm400540b |
| spellingShingle | Mistry, Shailesh N. Valant, Celine Sexton, Patrick M. Capuano, Ben Christopoulos, Arthur Scammells, Peter J. Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor |
| title | Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor |
| title_full | Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor |
| title_fullStr | Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor |
| title_full_unstemmed | Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor |
| title_short | Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor |
| title_sort | synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (bqca) as allosteric modulators of the m1 muscarinic receptor |
| url | https://eprints.nottingham.ac.uk/30413/ https://eprints.nottingham.ac.uk/30413/ https://eprints.nottingham.ac.uk/30413/ |