Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
We have shown that targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) can relieve memory loss in neurodegenerative disease and slow disease progression giving the promise that M1 mAChR agonists might be effective in Alzheimer's disease. In addition this receptor subtype also shows promise in the control of anxiety and hyper-locomotion associated with AD. Despite extensive efforts clinical trials and preclinical programmes have failed largely due to on-target adverse effects. Here we use genetically engineered mice that express receptor mutants showing functional signalling bias together with mice expressing M1 mAChR variants that only respond to selective chemical activation to define the signalling pathways that underlie M1 mAChR control of anxiety and locomotion. These model systems also revealed the importance of receptor phosphorylation in reducing cholinergic adverse responses, including M1 mAChR mediated seizures, which previously have been responsible for closure of drug discovery programmes. We conclude that targeting the M1 mAChR with selective ligands that bias receptor signalling towards receptor phosphorylation-dependent pathways might reduce adverse peripheral and central responses whilst maintaining clinically relevant efficacy in the control of anxiety and hyper-locomotion.
