Allosteric Modulation of Ligand Binding to Muscarinic Receptors

Allosteric ligands bind to a site on the receptor different from the primary (orthosteric) site. They modulate the binding and function of muscarinic receptors in a different way than orthosteric ligands. Unlike orthosteric ligands, their effects are limited by a cooperativity factor. This imparts them unique properties, including cooperativity-based selectivity, functional selectivity, and restoring of physiological-like space and time pattern of signaling under pathological conditions. Therefore, allosteric modulators of muscarinic receptors are intensively studied as possible therapeutics for pathological conditions including Alzheimer’s disease and schizophrenia. Research of allosteric modulation of muscarinic receptors has pioneered the way for a whole class A of G-protein coupled receptors and has had an impact beyond its field. In this chapter, we review the principles of allosteric modulation and its implications for the proper design of binding experiments and proper data analysis. We also discuss distinct properties of allosteric interactions that are specific to muscarinic receptors.