Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs

Bradley, Sophie J. and Molloy, Colin and Valuskova, Paulina and Dwomoh, Louis and Scarpa, Miriam and Rossi, Mario and Finlayson, Lisa and Svensson, Kjell A. and Chernet, Eyassu and Barth, Vanessa N. and Gherbi, Karolina and Sykes, David A. and Wilson, Caroline A. and Mistry, Raj and Sexton, Patrick M. and Christopoulos, Arthur and Mogg, Adrian J. and Rosenthorne, Elizabeth M. and Sakata, Shuzo and Challiss, R. A. John and Broad, Lisa M. and Tobin, Andrew B. (2020) Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs. Nature Chemical Biology, 16 (3). pp. 240-249. ISSN 1552-4450 (https://doi.org/10.1038/s41589-019-0453-9)

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Abstract

Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer’s disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including ‘epileptic-like’ seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD.

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