A golden age of muscarinic acetylcholine receptor modulation in neurological diseases

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. The M1 and M4 muscarinic acetylcholine receptors represent promising therapeutic targets for Alzheimer disease and schizophrenia. However, the development of agents targeting these receptors has been limited by their adverse cholinergic effects. Here, Tobin discusses how recent advances in the field — including an increased understanding of receptor biology and signalling, as well as the application of structure-based drug design — are enabling a new generation of muscarinic receptor modulators to enter clinical development.