Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases. (1st July 2018)

• Record Type: Journal Article
• Authors: Felder, Christian C.; Goldsmith, Paul J.; Jackson, Kimberley; Sanger, Helen E.; Evans, David A.; Mogg, Adrian J.; Broad, Lisa M.
• Is Part Of: Neuropharmacology. Volume 136:Part C(2018)
• Page Start: 449
• Page End: 458
• Publication Date: 2018-07-01
• Subjects: Muscarinic -- Receptor -- Acetylcholine -- M1 -- M4 -- Orthosteric -- Allosteric -- Preclinical -- Clinical -- Cognition -- Alzheimer -- Psychosis -- Neurodegenerative -- Neurology -- Neuropsychiatric; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.01.028
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: The cholinergic signalling system has been an attractive pathway to seek targets for modulation of arousal, cognition, and attention which are compromised in neurodegenerative and neuropsychiatric diseases. The acetylcholine muscarinic receptor M1 and M4 subtypes which are highly expressed in the central nervous system, in cortex, hippocampus and striatum, key areas of cognitive and neuropsychiatric control, have received particular attention. Historical muscarinic drug development yielded first generation agonists with modest selectivity for these two receptor targets over M2 and M3 receptors, the major peripheral sub-types hypothesised to underlie the dose-limiting clinical side effects. More recent compound screening and medicinal chemistry optimization of orthosteric and allosteric agonists, and positive allosteric modulators binding to sites distinct from the highly homologous acetylcholine binding pocket have yielded a collection of highly selective tool compounds for preclinical validation studies. Several M1 selective ligands have progressed to early clinical development and in time will hopefully lead to useful therapeutics for treating symptoms of Alzheimer's disease and related disorders. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'. Highlights: M1 and M4 receptors remain attractive targets for neurodegenerative and neuropsychiatric diseases. Targeting M1 receptors has focused on newer approaches such as the development of selective positive allosteric modulators. M4 receptors have received less attention, but agonists and positive allosteric modulators are being pursued.