Cholinergic muscarinic M1 and M4 receptors as therapeutic targets for cognitive, behavioural and psychological symptoms in psychiatric and neurological disorders

By Pradeep Nathan, Geor Bakker, Alastair Brown, Tim Tasker | Sep 9, 2019


Professor Pradeep Nathan, VP Clinical Development and Head of Experimental Medicine (Neuroscience) at Sosei Heptares, was recently invited to publish a Short Review in leading drug discovery journal, Drug Discovery Today, together with fellow Sosei Heptares colleagues including Geor Bakker, Alastair Brown and Tim Tasker and peers from the Institute of Neuroscience, Newcastle University in the UK. The review article titled "Cholinergic muscarinic M1 and M4 receptors as therapeutic targets for cognitive, behavioral and psychological symptoms in psychiatric and neurological disorders" provides an overview of the human cholinergic system and how it is affected in neuropsychiatric conditions, such as schizophrenia and several neurodegenerative disorders. In particular, the authors focus on the potential opportunities afforded by targeting cholinergic muscarinic receptors.


1) The cholinergic system is subject to extensive, though not uniform, neurodegeneration in many neuropsychiatric disorders.
2) Therapeutic targeting of the cholinergic system has typically relied on inhibition of acetylcholinesterase, which broadly increases all cholinergic activity.
3) Selective targeting of M1 and M4 muscarinic receptor sub-types may be effective in symptomatic relief in the disorders discussed, and may even have disease-modifying effects.


Cholinergic dysfunction is involved in a diverse range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease. This has led to the development of drugs targeting the cholinergic system for cognitive dysfunction in dementias. To date, drug development efforts targeting the cholinergic system has focused on increasing the availability of acetylcholine with cholinesterase inhibitors or targeting the nicotinic receptor sub-types, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders. We discuss how the selectivity of cholinergic system dysfunction suggests targeted cholinergic therapeutics to the muscarinic receptor subtypes may be vital in treating a number of disorders associated with cognitive dysfunction and behavioural and psychological symptoms.

Key words: Muscarinic receptors, M1, M4, cholinergic, schizophrenia, dementia, Lewy body disease

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