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Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs by Sophie J. Bradley; Colin Molloy; Paulina Valuskova; Louis Dwomoh; Miriam Scarpa; Mario Rossi; Lisa Finlayson; Kjell A. Svensson; Eyassu Chernet; Vanessa N. Barth; Karolina Gherbi; David A. Sykes; Caroline A. Wilson; Rajendra Mistry; Patrick M. Sexton; Arthur Christopoulos; Adrian J. Mogg; Elizabeth M. Rosethorne; Shuzo Sakata; R. A. John Challiss; Lisa M. Broad; Andrew B. Tobin is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs about?

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 th

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Author

Sophie J. Bradley; Colin Molloy; Paulina Valuskova; Louis Dwomoh; Miriam Scarpa; Mario Rossi; Lisa Finlayson; Kjell A. Svensson; Eyassu Chernet; Vanessa N. Barth; Karolina Gherbi; David A. Sykes; Caroline A. Wilson; Rajendra Mistry; Patrick M. Sexton; Arthur Christopoulos; Adrian J. Mogg; Elizabeth M. Rosethorne; Shuzo Sakata; R. A. John Challiss; Lisa M. Broad; Andrew B. Tobin

Publisher

Nature Publishing Group; Springer Science and Business Media LLC (ISSN 1552-4450)

Published

2020

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)