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

Autor: Bradley SJ; The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. sophie.bradley@glasgow.ac.uk., Molloy C; The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Valuskova P; The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Dwomoh L; The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Scarpa M; The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Rossi M; The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Finlayson L; The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Svensson KA; Eli Lilly & Co, Neuroscience Discovery, Lilly Corporate Center, Indianapolis, IN, USA., Chernet E; Eli Lilly & Co, Neuroscience Discovery, Lilly Corporate Center, Indianapolis, IN, USA., Barth VN; Eli Lilly & Co, Neuroscience Discovery, Lilly Corporate Center, Indianapolis, IN, USA., Gherbi K; School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.; Excellerate Bioscience Ltd, BioCity, Nottingham, UK., Sykes DA; School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.; Centre of Membrane and Protein and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK., Wilson CA; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK., Mistry R; Department of Molecular and Cell Biology, Henry Wellcome Building, University of Leicester, Leicester, UK., Sexton PM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia., Christopoulos A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia., Mogg AJ; Eli Lilly & Co, Neuroscience Discovery, Lilly Corporate Center, Indianapolis, IN, USA., Rosethorne EM; School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.; Centre of Membrane and Protein and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK., Sakata S; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK., John Challiss RA; Department of Molecular and Cell Biology, Henry Wellcome Building, University of Leicester, Leicester, UK., Broad LM; Eli Lilly & Co, Neuroscience Discovery, Erl Wood Manor, Windlesham, Surrey, UK., Tobin AB; The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. andrew.tobin@glasgow.ac.uk.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2020 Mar; Vol. 16 (3), pp. 240-249. Date of Electronic Publication: 2020 Feb 20.
DOI: 10.1038/s41589-019-0453-9
Abstrakt: 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.
Databáze: MEDLINE
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