Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development

Molecular-cloning studies have revealed the existence of five molecularly distinct mammalian muscarinic acetylcholine receptors (mAChRs), M1–M5, which are all members of the superfamily of class I (rhodopsin-like) G-protein-coupled receptors (GPCRs). Each of the five mAChR subtypes exhibits a distinct pattern of distribution and G-protein coupling/signalling profile.The mAChRs regulate many important central and peripheral functions including cognitive, behavioural, sensory, motor and autonomic processes, and the well-known actions of acetylcholine (ACh) on effector tissues innervated by parasympathetic nerves. Interestingly, changes in mAChR function have been implicated in several important pathophysiological disorders including Alzheimer's disease, Parkinson's disease, depression, schizophrenia, urinary incontinence and chronic obstructive pulmonary disease.Primarily owing to the lack of muscarinic ligands that have a high degree of selectivity for the individual mAChR subtypes, it is unclear in many cases which specific mAChR subtypes are involved in mediating the various muscarinic actions of ACh. However, such knowledge is essential for the rational design of novel muscarinic drugs with increased efficacy and reduced side effects.However, recent studies using mutant mouse strains deficient in each of the five mAChR subtypes have led to a wealth of novel information regarding the physiological and potential pathophysiological roles of the individual receptor subtypes. Importantly, such studies have identified specific mAChR-regulated pathways as potentially novel targets for the treatment of various important pathophysiological conditions including Alzheimer's disease, Parkinson's disease, schizophrenia and type 2 diabetes.Consequently, a major challenge remains in the development of small-molecule ligands exhibiting a high degree of selectivity for the individual mAChR subtypes. Such agents will probably include compounds that act on secondary (allosteric) sites that, in contrast to the classical (orthosteric) muscarinic binding site, are less well-conserved among the different mAChR subtypes.