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

Nat Chem Biol. 2020 Mar;16(3):240-249. doi: 10.1038/s41589-019-0453-9. Epub 2020 Feb 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy
  • Animals
  • Cholinergic Agents / pharmacology
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Disease Models, Animal
  • Drug Design
  • Female
  • Gene Knock-In Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Receptor, Muscarinic M1 / genetics*
  • Receptor, Muscarinic M1 / metabolism*


  • Cholinergic Agents
  • Cholinesterase Inhibitors
  • Receptor, Muscarinic M1
  • Acetylcholinesterase