Muscarinic Acetylcholine Receptors: Novel Opportunities for Drug Development Andrew C
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REVIEWS Muscarinic acetylcholine receptors: novel opportunities for drug development Andrew C. Kruse1,2, Brian K. Kobilka1, Dinesh Gautam3, Patrick M. Sexton4, Arthur Christopoulos4 and Jürgen Wess3 Abstract | The muscarinic acetylcholine receptors are a subfamily of G protein-coupled receptors that regulate numerous fundamental functions of the central and peripheral nervous system. The past few years have witnessed unprecedented new insights into muscarinic receptor physiology, pharmacology and structure. These advances include the first structural views of muscarinic receptors in both inactive and active conformations, as well as a better understanding of the molecular underpinnings of muscarinic receptor regulation by allosteric modulators. These recent findings should facilitate the development of new muscarinic receptor subtype-selective ligands that could prove to be useful for the treatment of many severe pathophysiological conditions. The muscarinic acetylcholine receptors (mAChRs) com- Recent studies with novel mAChR mouse models prise a family of five related G protein-coupled receptors have provided additional insights into the physiolog (GPCRs) belonging to the α-branch of class A GPCRs1. ical roles of the different mAChR subtypes4. Moreover, The mAChR family consists of five distinct subtypes, during the past few years, several laboratories have suc- denoted M1 to M5 (and encoded by the genes CHRM1 ceeded in developing ligands that show high selectivity 1 5,6 Department of Molecular to CHRM5). Three of these receptor subtypes (M1, M3 for specific mAChR subtypes . In contrast to conven- and Cellular Physiology, and M5) have been shown to couple to G proteins of the tional muscarinic receptor ligands, which bind to the Stanford University School G family, whereas the remaining two subtypes (M orthosteric receptor site, most of these new ligands bind of Medicine, Stanford, q/11 2 California 94305, USA. and M4) preferentially signal through the Gi/o family of to distinct allosteric sites. Such allosteric ligands can 2 2Present address: G proteins . The mAChRs have a central role in human influence the potency and efficacy of orthosteric ligands, Department of Biological physiology, regulating heart rate, smooth muscle con- and they may possess agonistic or inverse agonist activ- Chemistry and Molecular traction, glandular secretion and many fundamental ity in their own right. Interestingly, bitopic muscarinic Pharmacology, Harvard 3 Medical School, Boston, functions of the central nervous system (CNS) . receptor ligands with preference for certain subtypes 7–9 Massachusetts 02115, USA. Currently, drugs targeting muscarinic receptors are have also been developed recently . Such agents, which 3Molecular Signaling Section, used for the treatment of several pathophysiological con- can interact with both allosteric and orthosteric receptor Laboratory of Bioorganic ditions, including chronic obstructive pulmonary disease, sites simultaneously, offer new opportunities to target Chemistry, National Institute overactive bladder and Sjögren’s syndrome3. Despite the specific mAChR subtypes for therapeutic purposes. of Diabetes and Digestive and Kidney Diseases, powerful and diverse pharmacological actions of mus- The recent determination of the first mAChR struc- US National Institutes of carinic receptor agonists and antagonists, the development tures (M2 and M3 subtypes) represents a milestone in the Health, Bethesda, Maryland of these drugs for other clinical applications has prob- mAChR field10–12. These studies have provided the first 20892–0810, USA. ably been held back, at least in part, by the lack of small- molecular views of mAChRs in both their inactive10,11 and 4 Monash Institute of 12 Pharmaceutical Sciences molecule ligands that can inhibit or activate specific active conformations , revealing the molecular nature and Department of mAChRs with high selectivity. As a result, the precise of the binding sites for orthosteric muscarinic receptor Pharmacology, Monash physiological and pathophysiological roles of the individ- ligands. Moreover, structural and computational stud- University, Parkville, ual mAChR subtypes have, until recently, remained poorly ies have identified the mechanisms by which drug-like Victoria 3052, Australia. defined. However, during the past 15 years the generation allosteric modulators bind to the M subtype12,13. Correspondence to J.W. 2 e‑mail: [email protected] and phenotypic analysis of Chrm1- to Chrm5‑knockout In this Review, we summarize and discuss a series doi:10.1038/nrd4295 mice has been instrumental in improving our under of recent studies that have advanced our knowledge of Published online 6 June 2014 standing of the biology of the individual mAChRs3. mAChR biology, structure and pharmacology. In particular, NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | JULY 2014 | 549 © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS we emphasize the potential therapeutic implications of Chrm1‑knockout mice exhibited an age-dependent these novel findings. As mAChRs are prototypic class A cognitive decline in tasks that they performed normally GPCRs, the topics covered herein have implications for at a younger age17. Most importantly, several recent stud- other members of this receptor superfamily. ies have shown that compounds that act as PAMs at M1 receptors have cognition-enhancing activity in rodents Novel mAChR mouse models and are able to improve impaired cognition in mouse Since the late 1990s, studies with Chrm1- to Chrm5- models of Alzheimer’s disease18,19. Taken together, these knockout mice have elucidated many important physio new findings provide a rational basis for the develop- 3 logical functions of the individual mAChR subtypes . ment of M1-selective drugs (PAMs or agents that can The outcome of this work suggested that modulating activate M1 receptors directly) for the treatment of the activity of specific mAChR subtypes by selective Alzheimer’s disease and related disorders. ligands might prove to be beneficial for the treatment of many CNS disorders and other clinical conditions3. Schizophrenia. Schizophrenia, which is a chronic dis Until recently, essentially all phenotyping studies were abling brain disorder that affects ~1% of the general carried out with conventional, constitutive mAChR- population20, is characterized by enhanced central dopa- knockout mice, which lack one or more of the genes minergic signalling. Studies with conventional mAChR- encoding mAChRs throughout development in all cells knockout mice have indicated that the lack of central of the body. The proper interpretation of the phenotypes M1 and/or M4 receptors leads to a ‘dopamine hypersen- observed with conventional mAChR-knockout mice is sitivity phenotype’, which suggests that agents that can often complicated because individual mAChR subtypes enhance signalling through these receptor subtypes may are expressed in many different tissues and cell types, be endowed with antipsychotic activity3. In agreement and compensatory molecular or physiological changes with this concept, two clinical trials demonstrated that can occur during development. xanomeline, an M1- and M4-preferring muscarinic recep- To circumvent these difficulties, novel conditional tor agonist21, was effective in ameliorating psychosis-like knockout mice have been created that lack specific symptoms22,23. A recent study with cell type-specific mAChR subtypes only in certain tissues or cell types. Chrm4‑knockout mice strongly suggests that a distinct For these studies, mice containing ‘floxed’ versions of subpopulation of neuronal M4 receptors expressed by specific genes encoding mAChRs were crossed with D1 dopamine receptor-expressing neurons may be of transgenic mice expressing Cre recombinase in a cell particular importance in mediating the antipsychotic (TABLE 1) 24 type- or tissue-selective fashion . mAChR actions triggered by M4 receptor activation . In addition, knock-in mice have also been reported, in which the Dencker et al.25 reported that the antipsychotic-like effects native genes encoding M3 or M4 receptors — CHRM3 of xanomeline were almost completely abolished in two or CHRM4, respectively— were replaced with mutant mouse models of psychosis in which mice lacked M4 (TABLE 1) versions . Here, we summarize several recent receptors selectively in D1 receptor-expressing neurons. studies that have used novel mAChR-mutant mice as well In agreement with these findings, several recent preclini- as conventional mAChR-knockout mice. These studies cal studies suggest that PAMs of M1 and/or M4 receptors are discussed in the context of selected human diseases in may prove to be clinically useful for the treatment of which the development of novel classes of drugs targeting schizophrenia (reviewed in REFS 18,26–28). muscarinic receptors might be beneficial. Drug addiction. Acetylcholine has a key role in modulat- Targeting mAChRs in disease ing the neurochemical and behavioural CNS responses Alzheimer’s disease. Alzheimer’s disease, which is the to drugs of abuse29. Phenotypic analysis of Chrm5‑ most common form of dementia, is recognized as a major knockout mice suggested that centrally active M5 public health crisis14. At present, there are no drugs avail- receptor blockers might prove to be useful for the treat- able that are highly effective in preventing Alzheimer’s ment of drug abuse, including cocaine or opioid addic- disease or slowing its progress. Based on behavioural, tion3. More recent studies with