Ligand bias at the muscarinic acetylcholine receptor family: Opportunities and challenges

Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors (GPCRs) that are activated by the endogenous neurotransmitter, acetylcholine (ACh). Disruption of mAChR signalling has been associated with a variety of neurological disorders and non-neurological diseases. Consequently, the development of agonists and antagonists of the mAChRs has been a major avenue in drug discovery. Unfortunately, mAChR ligands are often associated with on-target side effects for two reasons. The first reason is due to the high sequence conservation at the orthosteric ACh binding site among all five receptor subtypes (M₁-M₅), making on-target subtype selectivity a major challenge. The second reason is due to on-target side effects of mAChR drugs that are associated with the pleiotropic nature of mAChR signalling at the level of a single mAChR subtype. Indeed, there is growing evidence that within the myriad of signalling events produced by mAChR ligands, some will have therapeutic benefits, whilst others may promote cholinergic side effects. This paradigm of drug action, known as ligand bias or biased agonism, is an attractive feature for next-generation mAChR drugs, as it holds the promise of developing drugs devoid of on-target adverse effects. Although relatively simple to detect and even quantify in vitro, ligand bias, as observed in recombinant systems, does not always translate to in vivo systems, which remains a major hurdle in GPCR drug discovery, including the mAChR family. Here we report recent studies that have attempted to detect and quantify ligand bias at the mAChR family, and briefly discuss the challenges associated with biased agonist drug development.

This article is part of the Special Issue on “Ligand Bias”.