Muscarinic Receptor Modulation in Neurological Disorders

Muscarinic acetylcholine receptors (mAChRs) constitute a family of five G protein-coupled receptors (M1–M5) that mediate the diverse actions of acetylcholine in the central nervous system. Dysregulation of these receptors has been implicated in Alzheimer’s disease, schizophrenia, addiction and other neuropsychiatric conditions. Conventional treatments aimed at elevating cholinergic tone often suffer poor selectivity and dose-limiting side effects. Recent advances have therefore focused on allosteric modulation, which enables subtype-specific tuning of receptor activity via non-orthosteric binding sites. This approach has yielded positive allosteric modulators (PAMs) that enhance receptor responses to endogenous acetylcholine without direct agonism, as well as negative allosteric modulators (NAMs) for dampening overactive pathways. Parallel developments in biased signalling seek to direct receptor coupling towards therapeutic intracellular cascades while avoiding adverse events. Structural elucidation of mAChR subtypes and the mapping of allosteric binding pockets have underpinned rational drug design. Collectively, these strategies offer the prospect of finely tailored interventions that restore cholinergic balance, improve cognition and alleviate psychotic or addictive behaviours with reduced peripheral toxicity.

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Muscarinic Receptor Modulation in Neurological Disorders publication trend

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Technical terms

Muscarinic receptor: A class of G protein-coupled acetylcholine receptors (M1–M5) implicated in central and peripheral cholinergic signalling.

Orthosteric site: The primary ligand-binding region on a receptor where endogenous neurotransmitters such as acetylcholine interact.

Allosteric modulator: A compound that binds to a secondary site on a receptor to alter the action of orthosteric ligands without directly activating the receptor.

Positive allosteric modulator (PAM): An agent that enhances the efficacy or affinity of an orthosteric agonist at its receptor.

Negative allosteric modulator (NAM): An agent that reduces the efficacy or affinity of an orthosteric agonist at its receptor.

Biased signalling: The preferential activation of certain intracellular signalling pathways over others by a receptor ligand.

References

1. Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias. Frontiers in Pharmacology (2021).
2. Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic. Trends in Pharmacological Sciences (2022).
3. Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. Translational Psychiatry (2022).