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A golden age of muscarinic acetylcholine receptor modulation in neurological diseases

Nature Reviews Drug Discovery (2024)Cite this article

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Abstract

Over the past 40 years, the muscarinic acetylcholine receptor family, particularly the M1-receptor and M4-receptor subtypes, have emerged as validated targets for the symptomatic treatment of neurological diseases such as schizophrenia and Alzheimer disease. However, despite considerable effort and investment, no drugs have yet gained clinical approval. This is largely attributable to cholinergic adverse effects that have halted the majority of programmes and resulted in a waning of interest in these G-protein-coupled receptor targets. Recently, this trend has been reversed. Driven by advances in structure-based drug design and an appreciation of the optimal pharmacological properties necessary to deliver clinical efficacy while minimizing adverse effects, a new generation of M1-receptor and M4-receptor orthosteric agonists and positive allosteric modulators are now entering the clinic. These agents offer the prospect of novel therapeutic solutions for ‘hard to treat’ neurological diseases, heralding a new era of muscarinic drug discovery.

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Fig. 1: Signalling downstream of the mAChR family.
Fig. 2: Mapping of in vivo bimodal signalling and downstream responses.
Fig. 3: Positive allosteric modulation of the M1-receptor.
Fig. 4: Structure-based drug design of the M1/M4-receptor orthosteric agonist HTL0009936.
Fig. 5: Building selectivity through agonist efficacy.

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Acknowledgements

The author thanks the Wellcome Trust, who provided a Collaborative Award (201529/Z/16/Z) to A.B.T., and the generous donations of the Rice family, and Alan and Ann Boyd. Thanks also to C. Jones (Vanderbilt University) for proofreading and advice.

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  1. Centre for Translational Pharmacology, School of Molecular Biosciences, The Advanced Research Centre, University of Glasgow, Glasgow, UK

    Andrew B. Tobin

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A.T. is fully employed by the University of Glasgow but is also co-founder and CEO of the spin-out company Keltic Pharma Therapeutics Ltd, which has an interest in targeting muscarinic receptors in neurological disease.

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Tobin, A.B. A golden age of muscarinic acetylcholine receptor modulation in neurological diseases. Nat Rev Drug Discov (2024). https://doi.org/10.1038/s41573-024-01007-1

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