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

Bradley, S. J. et al. (2020) Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs. Nature Chemical Biology, 16(3), pp. 240-249. (doi: 10.1038/s41589-019-0453-9) (PMID:32080630)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Rossi, Dr Mario and Finlayson, Mrs Lisa and Dwomoh, Dr Louis and Molloy, Mr Colin and Bradley, Dr Sophie and Valuskova, Ms Paulina and Tobin, Andrew and Scarpa, Miss Miriam
Authors: 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., Rosethorne, E. M., Sakata, S., Challiss, R. A. J., Broad, L. M., and Tobin, A. B.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Nature Chemical Biology
Publisher:Nature Research
ISSN (Online):1552-4469
Published Online:20 February 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Nature Chemical Biology 16(3): 240-249
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174202MICA Pharmacological, molecular and cellular mechanisms of muscarinic slowing (modification) of neurodegenerative disease.Andrew TobinMedical Research Council (MRC)MR/P019366/1Institute of Molecular, Cell & Systems Biology
173304Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical EfficacyAndrew TobinWellcome Trust (WELLCOTR)201529/Z/16/ZMCSB - Molecular Pharmacology