Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor.

Scammells, Peter J; Lane, J Robert; Mistry, Shailesh N; Lim, Herman; J�rg, Manuela; Capuano, Ben; Christopoulos, Arthur; Lane, J. Robert; Scammells, Peter J.

Abstract

Benzoquinazolinone 1 is a positive allosteric modulator (PAM) of the M1 muscarinic acetylcholine receptor (mAChR), which is significantly more potent than the prototypical PAM, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA). In this study, we explored the structural determinants that underlie the activity of 1 as a PAM of the M1 mAChR. We paid particular attention to the importance of the tricyclic scaffold of compound 1, for the activity of the molecule. Complete deletion of the peripheral fused benzene ring caused a significant decrease in affinity and binding cooperativity with acetylcholine (ACh). This loss of affinity was rescued with the addition of either one or two methyl groups in the 7- and/or 8-position of the quinazolin-4(3H)-one core. These results demonstrate that the tricyclic benzo[h]quinazolin-4(3H)-one core could be replaced with a quinazolin-4(3H)-one core and maintain functional affinity. As such, the quinazolin-4(3H)-one core represents a novel scaffold to further explore M1 mAChR PAMs with improved physicochemical properties.

Citation

Scammells, P. J., Lane, J. R., Mistry, S. N., Lim, H., Jörg, M., Capuano, B., Christopoulos, A., Lane, J. R., & Scammells, P. J. (2016). Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor. ACS Chemical Neuroscience, 7(5), 647-661. https://doi.org/10.1021/acschemneuro.6b00018

• Journal Article Type: Article
• Acceptance Date: Feb 18, 2016
• Online Publication Date: Feb 18, 2016
• Publication Date: 2016-02
• Deposit Date: Jun 13, 2016
• Publicly Available Date: Jun 13, 2016
• Journal: ACS Chemical Neuroscience
• Print ISSN: 1948-7193
• Electronic ISSN: 1948-7193
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 5
• Pages: 647-661
• DOI: https://doi.org/10.1021/acschemneuro.6b00018
• Public URL: https://nottingham-repository.worktribe.com/output/775857
• Publisher URL: http://pubs.acs.org/doi/abs/10.1021/acschemneuro.6b00018
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience, copyright © 2016 American Chemical Society ; after peer review and technical editing by the publisher. ; To access the final edited and published work see https://dx.doi.org/10.1021/acschemneuro.6b00018
• Contract Date: Jun 13, 2016