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

Authors
  • Mistry, Shailesh N1
  • Lim, Herman1
  • Jörg, Manuela1
  • Capuano, Ben1
  • Christopoulos, Arthur1
  • Lane, J Robert1
  • Scammells, Peter J1
  • 1 Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville 3052, Victoria Australia. , (Australia)
Type
Published Article
Journal
ACS Chemical Neuroscience
Publisher
American Chemical Society
Publication Date
May 18, 2016
Volume
7
Issue
5
Pages
647–661
Identifiers
DOI: 10.1021/acschemneuro.6b00018
PMID: 26891194
Source
Medline
Keywords
License
Unknown

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.

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