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

详细信息    查看全文

• 作者：Shailesh N. Mistry ; Herman Lim ; Manuela Jörg ; Ben Capuano ; Arthur Christopoulos ; J. Robert Lane ; Peter J. Scammells
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：May 18, 2016
• 年：2016
• 卷：7
• 期：5
• 页码：647-661
• 全文大小：635K
• 年卷期：0
• ISSN：1948-7193

文摘

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.