Targeting the M1 muscarinic receptor in neurodegenerative disease
By Sophie Bradley | Apr 12, 2022
Sophie Bradley, Translational Sciences Associate Director at Sosei Heptares, recently presented at the Keystone Symposia GPCR Conference, a summary of work performed both at Sosei Heptares and Glasgow University characterising the role of the muscarinic M1 receptor in cognitive and neurodegenerative disorders and the potential therapeutic benefit of muscarinic M1 selective ligands.
M1 muscarinic acetylcholine receptors are an established therapeutic target for improving cognitive decline in Alzheimer’s disease (AD). Attempts to target the M1-receptor clinically produced beneficial cognitive effects in AD and schizophrenia, but were hampered by cholinergic side effects. Our recent data shows that in addition to pro-cognitive benefits, M1-receptor ligands can display disease-modifying effects in preclinical models of neurodegenerative disease. Furthermore, we have developed a toolbox of chemogenetic and biased M1-receptor mutant mouse models to (i) fully understand the physiological role and therapeutic value of selective M1-receptor activation, and (ii) to define the pharmacological principles required in an M1-receptor ligand in order to mediate clinically beneficial effects and avoid adverse responses.