Muscarinic acetylcholine receptors are G-protein coupled receptors (GPCRs) located in the plasma membrane of many cell types of various tissues. These receptors mediate extracellular to intracellular signalling. Alterations in signalling via muscarinic receptors play an important role in a variety of neurological and psychiatric disorders, e.g. Alzheimer's disease, schizophrenia, and also in other internal diseases, e.g. asthma and overactive bladder.

Biased agonism: agonist A produces a biased stimulus for cellular signalling pathway 1, whereas agonist B produces another receptor conformation that selectively induces bias for cellular signalling pathway 2. (From Kenakin et Christopoulos 2013)

A biased agonist is a ligand which stabilizes a particular active conformation of a receptor, thus stimulating some responses but not others. Biased agonists might represent a novel and uniquely effective type of therapeutic agent with reduced side-effects. Several lines of evidence suggest that some muscarinic agonists, although they bind with the same affinity to all subtypes of the muscarinic receptor, activate individual subtypes to a different extent and display signalling bias. Understanding of the molecular mechanisms of signalling bias at muscarinic receptors may facilitate the development of desired functionally-selective antagonists and agonists.

Relavant publications:

T. Kenakin, A. Christopoulos, Signalling bias in new drug discovery: detection, quantification and therapeutic impact, Nat Rev Drug Discov. 12 (2013) 205–216.

E. Šantrůčková, V. Doležal, E.E. El-Fakahany, J. Jakubík, Long-Term Activation upon Brief Exposure to Xanomleline Is Unique to M1 and M4 Subtypes of Muscarinic Acetylcholine Receptors, PLoS One. 9 (2014) e88910.

A. Randáková, E. Dolejší, V. Rudajev, P. Zimčík, V. Doležal, E.E. El-Fakahany, J. Jakubík, Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms, Pharmacol Res. 97 (2015) 27–39.