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.

Abstract

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.

Citation

Mistry, S. N., Valant, C., Sexton, P. M., Capuano, B., Christopoulos, A., & Scammells, P. 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), https://doi.org/10.1021/jm400540b

• Journal Article Type: Article
• Publication Date: Jun 17, 2013
• Deposit Date: Oct 9, 2015
• Publicly Available Date: Oct 9, 2015
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 0022-2623
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 56
• Issue: 12
• DOI: https://doi.org/10.1021/jm400540b
• Public URL: https://nottingham-repository.worktribe.com/output/715708
• Publisher URL: http://pubs.acs.org/doi/abs/10.1021/jm400540b
• 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/abs/10.1021/jm400540b