Journal article

Development of Novel 4-Arylpyridin-2-one and 6-Arylpyrimidin-4-one Positive Allosteric Modulators of the M(1)Muscarinic Acetylcholine Receptor

Manuela Jorg, Elham Khajehali, Emma T van der Westhuizen, KH C. Choy, David M Shackleford, Andrew B Tobin, Patrick M Sexton, Celine Valant, Ben Capuano, Arthur Christopoulos, Peter J Scammells



This study investigated the structure-activity relationships of 4-phenylpyridin-2-one and 6-phenylpyrimidin-4-one M1 muscarinic acetylcholine receptor (M1 mAChRs) positive allosteric modulators (PAMs). The presented series focuses on modifications to the core and top motif of the reported leads, MIPS1650 (1) and MIPS1780 (2). Profiling of our novel analogues showed that these modifications result in more nuanced effects on the allosteric properties compared to our previous compounds with alterations to the biaryl pendant. Further pharmacological characterisation of the selected compounds in radioligand binding, IP1 accumulation and β-arrestin 2 recruitment assays demonstrated that, despite p..

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Awarded by Australian Research Council (ARC)

Awarded by National Health and Medicinal Research Council (NHMRC) of Australia

Awarded by Wellcome Trust Collaborative Research Award

Awarded by NHMRC

Funding Acknowledgements

This research was supported by Discovery grant DP110100687 of the Australian Research Council (ARC), Program grant APP1055134 and Project grant APP1049564 of the National Health and Medicinal Research Council (NHMRC) of Australia, and Wellcome Trust Collaborative Research Award (201529Z16Z). P.M.S. a Senior Principal Research Fellow, of the NHMRC. E.T.v.d.W. is an Early Career Researcher of the NHMRC (GNT1013819).