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

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, Raj Mistry, Patrick M. Sexton, Arthur Christopoulos, Adrian J. Mogg, Elizabeth M. Rosenthorne, Shuzo Sakata, R. A. John ChallissLisa M. Broad, Andrew B. Tobin

Research output: Contribution to journalArticle

2 Citations (Scopus)
1 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)240-249
Number of pages10
JournalNature Chemical Biology
Volume16
Issue number3
Early online date20 Feb 2020
DOIs
Publication statusPublished - 31 Mar 2020

Keywords

  • Alzheimer's disease
  • dementia
  • acetylcholine

Projects

Cite this

Bradley, S. J., Molloy, C., Valuskova, P., Dwomoh, L., Scarpa, M., Rossi, M., Finlayson, L., Svensson, K. A., Chernet, E., Barth, V. N., Gherbi, K., Sykes, D. A., Wilson, C. A., Mistry, R., Sexton, P. M., Christopoulos, A., Mogg, A. J., Rosenthorne, E. M., Sakata, S., ... Tobin, A. B. (2020). Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs. Nature Chemical Biology, 16(3), 240-249. https://doi.org/10.1038/s41589-019-0453-9