Journal article

6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M-1 mAChR: The Determinants of Allosteric Activity

Manuela Jorg, Emma T van der Westhuizen, Elham Khajehali, Wessel AC Burger, Jonathan M White, Kwok HC Choy, Andrew B Tobin, Patrick M Sexton, Celine Valant, Ben Capuano, Arthur Christopoulos, Peter J Scammells



Targeting allosteric sites of the M1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, an..

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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 (201529/Z/16/Z). A.C. is a Senior Principal Research Fellow, and P.M.S. a Principal Research Fellow, of the NHMRC. E.T.vdW is an Early Career Researcher of the NHMRC (GNT1013819). C.V. is an ARC Future Fellow.