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

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

Authors

Peter J Scammells

J Robert Lane

Herman Lim

Manuela Jörg

Ben Capuano

Arthur Christopoulos

J. Robert Lane

Peter J. Scammells



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.

Journal Article Type Article
Publication Date 2016-02
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
APA6 Citation Scammells, P. J., Lane, J. R., Mistry, S. N., Lim, H., Jörg, M., Capuano, B., …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
DOI https://doi.org/10.1021/acschemneuro.6b00018
Publisher URL http://pubs.acs.org/doi/abs/10.1021/acschemneuro.6b00018
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc/4.0
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

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc/4.0





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