Novel fused arylpyrimidinone based allosteric modulators of the M1 muscarinic acetylcholine receptor

Mistry, Shailesh N., Lim, Herman, Jörg, Manuela, Capuano, Ben, Christopoulos, Arthur, Lane, J. Robert and Scammells, Peter J. (2016) Novel fused arylpyrimidinone based allosteric modulators of the M1 muscarinic acetylcholine receptor. ACS Chemical Neuroscience, 7 (5). pp. 647-661. ISSN 1948-7193

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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.

Item Type: Article
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
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number:
Depositing User: Mistry, Dr Shailesh
Date Deposited: 13 Jun 2016 13:35
Last Modified: 04 May 2020 17:36

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