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Pejčić AV. Targeting muscarinic receptors in schizophrenia treatment: Novel antipsychotic xanomeline/trospium chloride. World J Psychiatry 2025; 15:105409. [DOI: 10.5498/wjp.v15.i6.105409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 04/04/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
This minireview explores the role of acetylcholine and muscarinic receptors in the pathophysiology of schizophrenia and summarizes the latest data on xanomeline/trospium chloride, a novel antipsychotic approved by the United States Food and Drug Administration in September 2024. Evidence suggests that cholinergic dysfunction, particularly an imbalance in the expression of the M1 and M4 muscarinic receptors, may contribute to the pathophysiology and symptoms of schizophrenia. Xanomeline/trospium chloride combines xanomeline, an M1 and M4 receptor agonist, with trospium chloride, a non-selective peripheral muscarinic receptor antagonist that reduces peripheral cholinergic side effects. Clinical trials have demonstrated significant reductions in the positive and negative symptoms of schizophrenia, with improvements in Positive and Negative Syndrome Scale scores observed as early as two weeks. A post-hoc analysis of one trial revealed cognitive improvements in patients with baseline cognitive impairment. This medication was generally well-tolerated, with mild-to-moderate gastrointestinal symptoms being the most common adverse events. While these results are promising, further research is needed to better understand its effectiveness and safety in real-world clinical practice, and to define its optimal role in managing this complex psychiatric disorder.
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Affiliation(s)
- Ana V Pejčić
- Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
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2
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Merz M, Playle C, Palchaudhuri M, Hucke O, Gross U, Ursu D. Downstream Signaling of Muscarinic M 4 Receptors Is Regulated by Receptor Density and Cellular Environment. Pharmacol Res Perspect 2025; 13:e70123. [PMID: 40384150 PMCID: PMC12086361 DOI: 10.1002/prp2.70123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/20/2025] Open
Abstract
Multiple muscarinic M4 receptor modulators are currently advancing in clinical development for the treatment of positive symptoms in schizophrenia, including agonists and positive allosteric modulators. Considering the importance of comprehending M4 receptor pharmacology for these therapeutic applications, this study investigates M4 receptor signaling pathways upon activation by structurally diverse muscarinic agonists, exploring the role of receptor expression levels and cellular environment on downstream signaling. HEK-293 cells and rat primary neurons expressing human M4 receptors were used to measure the kinetics of cAMP levels and compound effects on neuronal network activity. Receptor expression levels were controlled by a Tet-On system and quantified using a radioactive binding assay. Our findings revealed that most agonists caused a concentration-dependent reduction of cAMP levels (Gi/o) at low concentrations, while inducing an increase in cAMP at higher concentrations (Gs). A less prominent coupling via Gs was observed when receptor density in HEK-293 cells was reduced. In the neuronal assay, most compounds showed consistent inhibition of neuronal activity. A distinct group of agonists displayed a specific profile, with no Gs coupling at high receptor density, partial activation at low receptor density, and low to no effects in the neuronal assay. This study provides a side-by-side comparison of the activity of structurally diverse M4 agonists and highlights compound-specific activation of GPCR intracellular signaling pathways. The data offer new insights into M4 receptor pharmacology that may aid in the development of novel therapies for the treatment of psychiatric diseases.
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Affiliation(s)
- Madeleine Merz
- Boehringer Ingelheim Pharma GmbH & Co. KGDiv. Research GermanyBiberach an der RissGermany
| | - Charlotte Playle
- Boehringer Ingelheim Pharma GmbH & Co. KGDiv. Research GermanyBiberach an der RissGermany
| | - Monika Palchaudhuri
- Boehringer Ingelheim Pharma GmbH & Co. KGDiv. Research GermanyBiberach an der RissGermany
| | - Oliver Hucke
- Boehringer Ingelheim Pharma GmbH & Co. KGDiv. Research GermanyBiberach an der RissGermany
| | - Ulrike Gross
- Boehringer Ingelheim Pharma GmbH & Co. KGDiv. Research GermanyBiberach an der RissGermany
| | - Daniel Ursu
- Boehringer Ingelheim Pharma GmbH & Co. KGDiv. Research GermanyBiberach an der RissGermany
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Zhu M, Wu M, Yang A, Tu Y, Sun C, Na Y, Zhang Y, Wang Y, Su H, Liu X. (+)-a-Longipinene alleviates murine laser-induced choroidal neovascularization: Evidence from in vivo and in vitro experiments. Int Immunopharmacol 2025; 159:114913. [PMID: 40412129 DOI: 10.1016/j.intimp.2025.114913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 05/05/2025] [Accepted: 05/18/2025] [Indexed: 05/27/2025]
Abstract
Choroidal neovascularization (CNV) is a progressive, degenerative pathological change. CNV can lead to severe vision loss, even blindness. (+)-a-Longipinene (LON) is an essential oil isolated from Pinus koraiensis and Hypericum. It plays anti-inflammatory and anti-angiogenic roles. Here, we attempted to identify the role and mechanism of action of (+)-a-LON in a murine model of laser-induced CNV as well as in vitro in hypoxic human choroidal endothelial cells (HCECs). (+)-a-LON alleviated the formation of laser-induced CNV in mice without causing ocular and systemic toxicity. Moreover, (+)-a-LON inhibited the production of fibroblast growth factor 2 (FGF2) in hypoxic human HCECs by downregulating the M3 muscarinic acetylcholine receptor (M3 mAchR)/diacylglycerol (DAG)/protein kinase C alpha (PKCα)/E1A-binding protein P300 (EP300) pathway. Notably, (+)-a-LON inhibited the hypoxia-induced proliferation, migration, and tube formation of HCECs and also suppressed inflammatory responses in the cells by downregulating the M3 mAchR/DAG/PKCα/EP300/FGF2 pathway. Briefly, (+)-a-LON attenuated the symptoms of CNV possibly by blocking the M3 mAchR/DAG/PKCα/EP300/FGF2 pathway in CECs.
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Affiliation(s)
- Manhui Zhu
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, 215123, Suzhou, Jiangsu, China
| | - Min Wu
- Department of Pathogen Biology, Medical College, Nantong University, 226001, Nantong, Jiangsu, China
| | - Aimin Yang
- Department of Ophthalmology, Binhai County Hospital of Traditional Chinese Medicine, 224500 Cheng Yan, Jiangsu, China
| | - Yuanyuan Tu
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, 215123, Suzhou, Jiangsu, China
| | - Cuilian Sun
- Department of Pathogen Biology, Medical College, Nantong University, 226001, Nantong, Jiangsu, China
| | - Yuhang Na
- Department of Pathogen Biology, Medical College, Nantong University, 226001, Nantong, Jiangsu, China
| | - Yuting Zhang
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, 215123, Suzhou, Jiangsu, China
| | - Yufei Wang
- Department of Pathogen Biology, Medical College, Nantong University, 226001, Nantong, Jiangsu, China
| | - Hui Su
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, 215123, Suzhou, Jiangsu, China..
| | - Xiaojuan Liu
- Department of Pathogen Biology, Medical College, Nantong University, 226001, Nantong, Jiangsu, China.
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Sharma S, Wadkar A, Kommajosyula SP. Muscarinic receptors at the auditory thalamocortical circuits and relevance to hearing. Life Sci 2025; 369:123522. [PMID: 40044029 DOI: 10.1016/j.lfs.2025.123522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/25/2025] [Accepted: 03/01/2025] [Indexed: 03/09/2025]
Abstract
The auditory thalamus and cortex are the critical structures in the auditory hierarchy, owing to their crucial role in plasticity, auditory object formation, speech understanding, and spatiotemporal integration. Acetylcholine, a key neuromodulator, alters the abovementioned processes by orchestrating its effects with other neurotransmitters and its high-affinity receptor, the muscarinic receptor. This manuscript extensively covers the localization and function of different muscarinic receptors in the auditory thalamocortical system. Gaps in research of muscarinic localization and function are identified in hearing function. Also, a scarcity of studies examining muscarinic structure and function with tinnitus and hearing loss (age-related/noise-induced) is presented. Central changes in neurotransmitter receptors and auditory coding occur due to maladaptive plasticity in hearing loss and tinnitus and alter auditory object formation and spatiotemporal discrimination behaviors. Addressing these gaps are key to developing therapeutic strategies for hearing loss and tinnitus, apart from rectifying cochlear insult that led to hearing loss/tinnitus. Focusing on the muscarinic receptors is important owing to their abundance and demonstrated functional role in the auditory thalamocortical circuits and cortical development in mutant mice. In conclusion, this review emphasizes the need to answer questions on the localization and function of muscarinic receptors.
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Affiliation(s)
- Shivani Sharma
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar, Medchal District, Hyderabad 500078, India
| | - Avinash Wadkar
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar, Medchal District, Hyderabad 500078, India
| | - Srinivasa Prasad Kommajosyula
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar, Medchal District, Hyderabad 500078, India.
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Fisher A, Levey AI. CNS muscarinic receptors and muscarinic receptor agonists in Alzheimer disease treatment. HANDBOOK OF CLINICAL NEUROLOGY 2025; 211:161-184. [PMID: 40340060 DOI: 10.1016/b978-0-443-19088-9.00016-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
This review explores the main aspects that form the basis of the cholinergic-oriented treatment of Alzheimer disease. Muscarinic acetylcholine receptor subtypes in the brain and periphery are discussed. It includes a new and updated overview of the involvement of muscarinic receptors in Alzheimer disease and the recent development of new and highly selective M1 muscarinic receptor agonists with disease-modifying potential. Activation of the M1 muscarinic receptor is a rational therapeutic strategy for the treatment of schizophrenia and Alzheimer disease, as this receptor plays a pivotal role in modulating cognitive deficits and the pathology of the disease. Such activation can be achieved through M1 allosteric and bitopic muscarinic agonists, M1 positive allosteric modulators (M1 PAMs), and direct-acting M1 muscarinic orthosteric agonists. The efficacy of M1 PAMs depends on acetylcholine, which declines in Alzheimer disease as postsynaptic neurons lose cholinergic input from the basal forebrain. On the other hand, the activity of M1 muscarinic orthosteric agonists is independent of the functional or anatomic integrity of presynaptic cholinergic terminals, and likely retain efficacy as the disease progresses, even after presynaptic degeneration of cholinergic fibers. Based on the acceptance criteria for a preferred M1 muscarinic agonist for the treatment of AD, aiming for efficacy, specificity, and safety in clinical use, few M1 muscarinic agonists fulfill these requirements, such as orthosteric M1 agonists-cevimeline (aka AF102B), the first FDA-approved M1 agonist, and NSC001 (aka AF267B). The pros and cons of various muscarinic agonists developed are critically discussed in comparison to these drugs. The review proposes new alternatives to cholinergic therapy, particularly selective M1 muscarinic drugs, that should be designed to amplify its clinical effect and supplement the disease-modifying effect of new treatments to slow down or arrest disease progression.
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Affiliation(s)
- Abraham Fisher
- ADPD: Advances in Science & Therapy, International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders, Lisbon, Portugal.
| | - Allan I Levey
- Department of Neurology, Emory University, Atlanta, GA, United States
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Vahid ZF, Eskandani M, Dadashi H, Vandghanooni S, Rashidi MR. Recent advances in potential enzymes and their therapeutic inhibitors for the treatment of Alzheimer's disease. Heliyon 2024; 10:e40756. [PMID: 39717593 PMCID: PMC11664286 DOI: 10.1016/j.heliyon.2024.e40756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 11/23/2024] [Accepted: 11/26/2024] [Indexed: 12/25/2024] Open
Abstract
Alzheimer's disease (AD), a chronic neurodegenerative disease, is clinically characterized by loss of memory and learning ability among other neurological deficits. Amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles involve in AD etiology. Meanwhile, enzymes and their inhibitors have become the focus of research in AD treatment. In this review, the molecular mechanisms involved in the pathogenesis of AD were overviewed and various enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase, γ-secretase, monoamine oxidase (MAO), and receptor of advanced glycation end products (RAGE) were highlighted as potential targets for AD treatment. Several hybrid molecules with essential substructures derived from various chemotypes have demonstrated desired pharmacological activity. It is envisioned that the development of new drugs that inhibit enzymes involved in AD is a future trend in the management of the disease.
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Affiliation(s)
| | - Morteza Eskandani
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Dadashi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Vandghanooni
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad-Reza Rashidi
- Medicinal Chemistry Department, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
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Yuen GKW, Lin S, Dong TTX, Tsim KWK. Sophoricoside, a genistein glycoside from Fructus Sophorae, promotes hair growth via activation of M4 muscarinic AChR in dermal papilla cells. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118585. [PMID: 39019417 DOI: 10.1016/j.jep.2024.118585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/08/2024] [Accepted: 07/14/2024] [Indexed: 07/19/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Alopecia, or hair loss, refers to ongoing decline of mature hair on the scalp or any other region of the body. Fructus Sophorae, a fruit from Sophora japonica L., contains various phytochemicals, e.g., sophoricoside, that exhibit a broad range of pharmacological effects. The potential functions of herbal extracts deriving from Fructus Sophorae and/or its major phytochemical, sophoricoside, in treating alopecia are probed here. AIM OF STUDY The objective was to determine the ability of Fructus Sophorae extract and sophoricoside in promoting hair growth and it signalling mechanism. METHODS Molecular docking studies were conducted to measure the binding affinities between sophoricoside and M4 mAChR in the allosteric binding site. The mechanism of Fructus Sophorae and sophoricoside in activating the signalling involving Wnt/β-catenin and muscarinic AChR was evaluated by using immortalized human dermal papilla cell line (DPC), as well as their roles in promoting hair growth. The activity of pTOPflash-luciferase in transfected DPCs was used to examine the transcriptional regulation of Wnt/β-catenin-mediated genes. RT-PCR was applied to quantify mRNA expressions of the biomarkers in DPCs responsible for hair growth. The phosphorylated protein levels of Wnt/β-catenin and PI3K/AKT in DPC were revealed by using Western blot analysis. The culture of ex vivo mouse vibrissae hair follicle was used to evaluate the hair growth after the treatments. RESULTS The ethanol extract of Fructus Sophorae and sophoricoside activated Wnt/β-catenin signalling. The result of molecular docking showed a high binding affinity between sophoricoside and M4 mAChR. The effect of sophoricoside was blocked by specific inhibitor of M4 mAChR, but not by other inhibitors of mAChRs. Sophoricoside promoted hair growth in cultured ex vivo mouse vibrissae hair follicle by acting through M4 mAChR. CONCLUSION The ethanol extract of Fructus Sophorae and sophoricoside activated Wnt/β-catenin signalling via activation of M4 mAChR. The results suggested beneficial functions of Fructus Sophorae and sophoricoside as a potential candidate in treating alopecia.
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Affiliation(s)
- Gary Ka-Wing Yuen
- Division of Life Science, Centre for Chinese Medicine, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Shenzhen, 518057, China.
| | - Shengying Lin
- Division of Life Science, Centre for Chinese Medicine, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Shenzhen, 518057, China.
| | - Tina Ting-Xia Dong
- Division of Life Science, Centre for Chinese Medicine, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Shenzhen, 518057, China.
| | - Karl Wah-Keung Tsim
- Division of Life Science, Centre for Chinese Medicine, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Shenzhen, 518057, China.
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Walker LC, Huckstep KL, Becker HC, Langmead CJ, Lawrence AJ. Targeting muscarinic receptors for the treatment of alcohol use disorders: Opportunities and hurdles for clinical development. Br J Pharmacol 2024; 181:4385-4398. [PMID: 37005377 DOI: 10.1111/bph.16081] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/04/2023] Open
Abstract
Emerging evidence suggests muscarinic acetylcholine receptors represent novel targets to treat alcohol use disorder. In this review, we draw from literature across medicinal chemistry, molecular biology, addiction and learning/cognition fields to interrogate the proposition for muscarinic receptor ligands in treating various aspects of alcohol use disorder, including cognitive dysfunction, motivation to consume alcohol and relapse. In support of this proposition, we describe cholinergic dysfunction in the pathophysiology of alcohol use disorder at a network level, including alcohol-induced adaptations present in both human post-mortem brains and reverse-translated rodent models. Preclinical behavioural pharmacology implicates specific muscarinic receptors, in particular, M4 and M5 receptors, as potential therapeutic targets worthy of further interrogation. We detail how these receptors can be selectively targeted in vivo by the use of subtype-selective allosteric modulators, a strategy that overcomes the issue of targeting a highly conserved orthosteric site bound by acetylcholine. Finally, we highlight the intense pharma interest in allosteric modulators of muscarinic receptors for other indications that provide an opportunity for repurposing into the alcohol use disorder space and provide some currently unanswered questions as a roadmap for future investigation.
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Affiliation(s)
- Leigh C Walker
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Kade L Huckstep
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Howard C Becker
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Christopher J Langmead
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Andrew J Lawrence
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
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Ongnok B, Prathumsap N, Chunchai T, Pantiya P, Arunsak B, Chattipakorn N, Chattipakorn SC. Nicotinic and Muscarinic Acetylcholine Receptor Agonists Counteract Cognitive Impairment in a Rat Model of Doxorubicin-Induced Chemobrain via Attenuation of Multiple Programmed Cell Death Pathways. Mol Neurobiol 2024; 61:8831-8850. [PMID: 38568417 DOI: 10.1007/s12035-024-04145-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 03/21/2024] [Indexed: 10/23/2024]
Abstract
Chemotherapy causes undesirable long-term neurological sequelae, chemotherapy-induced cognitive impairment (CICI), or chemobrain in cancer survivors. Activation of programmed cell death (PCD) has been proposed to implicate in the development and progression of chemobrain. Neuronal apoptosis has been extensively recognized in experimental models of chemobrain, but little is known about alternative forms of PCD in response to chemotherapy. Activation of acetylcholine receptors (AChRs) is emerging as a promising target in attenuating a wide variety of the neuronal death associated with neurodegeneration. Thus, this study aimed to investigate the therapeutic capacity of AChR agonists on cognitive function and molecular hallmarks of multiple PCD against chemotherapy neurotoxicity. To establish the chemobrain model, male Wistar rats were assigned to receive six doses of doxorubicin (DOX: 3 mg/kg) via intraperitoneal injection. The DOX-treated rats received either an a7nAChR agonist (PNU-282987: 3 mg/kg/day), mAChR agonists (bethanechol: 12 mg/kg/day), or the two as a combined treatment. DOX administration led to impaired cognitive function via neuroinflammation, glial activation, reduced synaptic/blood-brain barrier integrity, defective mitochondrial ROS-detoxifying capacity, and dynamic imbalance. DOX insult also mediated hyperphosphorylation of Tau and simultaneously induced various PCD, including apoptosis, necroptosis, and pyroptosis in the hippocampus. Concomitant treatment with either PNU-282987, bethanechol, or a combination of the two potently attenuated neuroinflammation, mitochondrial dyshomeostasis, and Tau hyperphosphorylation, thereby suppressing excessive apoptosis, necroptosis, and pyroptosis and improving cognitive function in DOX-treated rats. Our findings suggest that activation of AChRs using their agonists effectively protected against DOX-induced neuronal death and chemobrain.
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Affiliation(s)
- Benjamin Ongnok
- Neuroelectrophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
| | - Nanthip Prathumsap
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
| | - Titikorn Chunchai
- Neuroelectrophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
| | - Patcharapong Pantiya
- Neuroelectrophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
| | - Busarin Arunsak
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Neuroelectrophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand.
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand.
- Cardiac Electrophysiology Unit, Department of Physiology, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand.
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Mueang Chiang Mai, 50200, Chiang Mai, Thailand.
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Zhang J, Zhang Y, Wang J, Xia Y, Zhang J, Chen L. Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. Signal Transduct Target Ther 2024; 9:211. [PMID: 39174535 PMCID: PMC11344989 DOI: 10.1038/s41392-024-01911-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 03/18/2024] [Accepted: 07/02/2024] [Indexed: 08/24/2024] Open
Abstract
Alzheimer's disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate and diverse, stemming from a combination of factors such as aging, genetics, and environment. Our current understanding of AD pathologies involves various hypotheses, such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Nonetheless, unraveling the interplay among these pathological aspects and pinpointing the primary initiators of AD require further elucidation and validation. In the past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available drugs primarily offer symptomatic relief and often accompanied by undesirable side effects. However, recent approvals of aducanumab (1) and lecanemab (2) by the Food and Drug Administration (FDA) present the potential in disrease-modifying effects. Nevertheless, the long-term efficacy and safety of these drugs need further validation. Consequently, the quest for safer and more effective AD drugs persists as a formidable and pressing task. This review discusses the current understanding of AD pathogenesis, advances in diagnostic biomarkers, the latest updates of clinical trials, and emerging technologies for AD drug development. We highlight recent progress in the discovery of selective inhibitors, dual-target inhibitors, allosteric modulators, covalent inhibitors, proteolysis-targeting chimeras (PROTACs), and protein-protein interaction (PPI) modulators. Our goal is to provide insights into the prospective development and clinical application of novel AD drugs.
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Affiliation(s)
- Jifa Zhang
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yinglu Zhang
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, TN, USA
| | - Yilin Xia
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jiaxian Zhang
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lei Chen
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Liu B, Thompson G, Jörg M, Barnes N, Thal DM, Christopoulos A, Capuano B, Valant C, Scammells PJ. Discovery of 2-Methyl-5-(1 H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M 4 mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders. J Med Chem 2024. [PMID: 39023902 DOI: 10.1021/acs.jmedchem.4c01207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
The M4 muscarinic acetylcholine receptor (mAChR) is a biological target for neurocognitive disorders. Compound 1 is an ago-PAM for the M4 mAChR. Herein, we report the design, synthesis, and evaluation of novel putative M4 mAChR PAMs based on 1. These analogs were screened and then fully characterized in two functional assays (GoB protein activation and CAMYEL activation) to quantify their allosteric and ago-PAM properties against ACh. A selection of 7 M4 PAMs were assessed for their ability to modulate ACh-mediated β-arrestin recruitment and revealed 4 distinct clusters of M4 PAM activity: (1) analogs similar to 1 (24d), (2) analogs demonstrating only allosteric agonism (23d), (3) analogs with increased allosteric properties in CAMYEL activation (23b/23f and 24a/24b), and (4) analogs with a biased modulatory effect toward β-arrestin recruitment (23i). These novel M4 chemical tools disclose discrete molecular determinants, allowing further interrogation of the therapeutic roles of cAMP and β-arrestin pathways in neurocognitive disorders.
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Affiliation(s)
- Boqun Liu
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Geoff Thompson
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Manuela Jörg
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Nicholas Barnes
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - David M Thal
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
- Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Arthur Christopoulos
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
- Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Ben Capuano
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Celine Valant
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
- Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Peter J Scammells
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
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12
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Nguyen HTM, van der Westhuizen ET, Langmead CJ, Tobin AB, Sexton PM, Christopoulos A, Valant C. Opportunities and challenges for the development of M 1 muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits. Br J Pharmacol 2024; 181:2114-2142. [PMID: 36355830 DOI: 10.1111/bph.15982] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/22/2022] [Accepted: 10/18/2022] [Indexed: 11/12/2022] Open
Abstract
Targeting allosteric sites of M1 muscarinic acetylcholine receptors (M1 receptors) is a promising strategy to treat neurocognitive disorders, such as Alzheimer's disease and schizophrenia. Indeed, the last two decades have seen an impressive body of work focussing on the design and development of positive allosteric modulators (PAMs) for the M1 receptor. This has led to the identification of a structurally diverse range of highly selective M1 PAMs. In preclinical models, M1 PAMs have shown rescue of cognitive deficits and improvement of endpoints predictive of symptom domains of schizophrenia. Yet, to date only a few M1 PAMs have reached early-stage clinical trials, with many of them failing to progress further due to on-target mediated cholinergic adverse effects that have plagued the development of this class of ligand. This review covers the recent preclinical and clinical studies in the field of M1 receptor drug discovery for the treatment of Alzheimer's disease and schizophrenia, with a specific focus on M1 PAM, highlighting both the undoubted potential but also key challenges for the successful translation of M1 PAMs from bench-side to bedside. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
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Affiliation(s)
- Huong T M Nguyen
- Drug Discovery Biology, Monash University, Parkville, Melbourne, VIC, Australia
- Department of Biochemistry, Hanoi University of Pharmacy, Hanoi, Vietnam
| | | | - Christopher J Langmead
- Drug Discovery Biology, Monash University, Parkville, Melbourne, VIC, Australia
- Neuromedicines Discovery Centre, Monash University, Parkville, Melbourne, VIC, Australia
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash University, Parkville, Melbourne, VIC, Australia
| | - Andrew B Tobin
- Centre for Translational Pharmacology, University of Glasgow, Glasgow, UK
| | - Patrick M Sexton
- Drug Discovery Biology, Monash University, Parkville, Melbourne, VIC, Australia
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash University, Parkville, Melbourne, VIC, Australia
| | - Arthur Christopoulos
- Drug Discovery Biology, Monash University, Parkville, Melbourne, VIC, Australia
- Neuromedicines Discovery Centre, Monash University, Parkville, Melbourne, VIC, Australia
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash University, Parkville, Melbourne, VIC, Australia
| | - Celine Valant
- Drug Discovery Biology, Monash University, Parkville, Melbourne, VIC, Australia
- Neuromedicines Discovery Centre, Monash University, Parkville, Melbourne, VIC, Australia
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13
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Azargoonjahromi A. Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment. Clin Drug Investig 2024; 44:471-493. [PMID: 38904739 DOI: 10.1007/s40261-024-01377-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2024] [Indexed: 06/22/2024]
Abstract
Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.
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Affiliation(s)
- Ali Azargoonjahromi
- Shiraz University of Medical Sciences, Janbazan Blv, 14th Alley, Jahrom, Shiraz, 7417773539, Fars, Iran.
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14
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Shen S, Wu C, Lin G, Yang X, Zhou Y, Zhao C, Miao Z, Tian X, Wang K, Yang Z, Liu Z, Guo N, Li Y, Xia A, Zhou P, Liu J, Yan W, Ke B, Yang S, Shao Z. Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1. Proc Natl Acad Sci U S A 2024; 121:e2321532121. [PMID: 38830102 PMCID: PMC11181136 DOI: 10.1073/pnas.2321532121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/01/2024] [Indexed: 06/05/2024] Open
Abstract
Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and β-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.
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Affiliation(s)
- Siyuan Shen
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu610212, Sichuan, China
| | - Chao Wu
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Guifeng Lin
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Xin Yang
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Yangli Zhou
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Chang Zhao
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Zhuang Miao
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Xiaowen Tian
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Kexin Wang
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Zhiqian Yang
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Zhiyu Liu
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Nihong Guo
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Yueshan Li
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Anjie Xia
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Pei Zhou
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Jingming Liu
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Wei Yan
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Bowen Ke
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
| | - Shengyong Yang
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu610212, Sichuan, China
| | - Zhenhua Shao
- Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, Sichuan, China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu610212, Sichuan, China
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15
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Kenakin T. Bias translation: The final frontier? Br J Pharmacol 2024; 181:1345-1360. [PMID: 38424747 DOI: 10.1111/bph.16335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 10/24/2023] [Accepted: 10/31/2023] [Indexed: 03/02/2024] Open
Abstract
Biased signalling is a natural result of GPCR allosteric function and should be expected from any and all synthetic and natural agonists. Therefore, it may be encountered in all agonist discovery projects and must be considered as a beneficial (or possible detrimental) feature of new candidate molecules. While bias is detected easily, the synoptic nature of GPCR signalling makes translation of simple in vitro bias to complex in vivo systems problematic. The practical outcome of this is a difficulty in predicting the therapeutic value of biased signalling due to the failure of translation of identified biased signalling to in vivo agonism. This is discussed in this review as well as some new ways forward to improve this translation process and better exploit this powerful pharmacologic mechanism.
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Affiliation(s)
- Terry Kenakin
- Department of Pharmacology, University of North Carolina, School of Medicine, Chapel Hill, North Carolina, USA
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16
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Leber A, Ramachandra R, Ceban F, Kwan ATH, Rhee TG, Wu J, Cao B, Jawad MY, Teopiz KM, Ho R, Le GH, Ramachandra D, McIntyre RS. Efficacy, safety, and tolerability of xanomeline for schizophrenia spectrum disorders: a systematic review. Expert Opin Pharmacother 2024; 25:467-476. [PMID: 38515004 DOI: 10.1080/14656566.2024.2334424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 03/20/2024] [Indexed: 03/23/2024]
Abstract
INTRODUCTION We systematically reviewed extant studies evaluating the efficacy and tolerability of xanomeline and xanomeline-trospium (KarXT) for treatment of adults with schizophrenia. METHODS In accordance with PRISMA guidelines, articles were systematically searched for in databases and clinical trial registries. RESULTS A total of 4 preclinical trials and 3 randomized controlled trials (RCTs) were included in this review. A 4-week RCT observed a difference of 24.0 points (SD 21.0) in the Positive and Negative Syndrome Scale (PANSS) total score between xanomeline and placebo groups (p = 0.039). A 5-week RCT observed PANSS total score changes from baseline to week 5, including -17.4 and -5.9 points in KarXT and placebo groups, respectively (LSMD -11.6 points; 95% CI -16.1 to -7.1; p < 0.001; d = 0.75). Another 5-week RCT observed PANSS total score changes from baseline to week 5, including -21.2 (SE 1.7) and -11.6 (SE 1.6) points in KarXT and placebo groups, respectively (LSMD -9.6; 95% CI -13.9 to -5.2; p < 0.0001; d = 0.61). Side effects include constipation, nausea, vomiting, dyspepsia, and dry mouth. CONCLUSION KarXT offers an innovative non-D2 blocking approach, representing a promising treatment avenue for schizophrenia.
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Affiliation(s)
- Alexia Leber
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
- Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
| | - Ranuk Ramachandra
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
- Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
| | - Felicia Ceban
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
- Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Angela T H Kwan
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
- Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Taeho Greg Rhee
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Jie Wu
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Bing Cao
- School of Psychology and Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing, P. R. China
| | - Muhammad Youshay Jawad
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
- Institute for Mental Health Policy Research, Centre for Addictions and Mental Health, Toronto, Ontario, Canada
- Department of Psychiatry and Behavioral Health, Penn State University College of Medicine, Hershey, PA, USA
| | - Kayla M Teopiz
- Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
| | - Roger Ho
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore
| | - Gia Han Le
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
- Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Diluk Ramachandra
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
| | - Roger S McIntyre
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
- Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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17
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Fisher CL, Pavan M, Salmaso V, Keyes RF, Wan TC, Pradhan B, Gao ZG, Smith BC, Jacobson KA, Auchampach JA. Extrahelical Binding Site for a 1 H-Imidazo[4,5-c]quinolin-4-amine A 3 Adenosine Receptor Positive Allosteric Modulator on Helix 8 and Distal Portions of Transmembrane Domains 1 and 7. Mol Pharmacol 2024; 105:213-223. [PMID: 38182432 PMCID: PMC10877738 DOI: 10.1124/molpharm.123.000784] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 11/27/2023] [Accepted: 12/12/2023] [Indexed: 01/07/2024] Open
Abstract
This study describes the localization and computational prediction of a binding site for the A3 adenosine receptor (A3AR) positive allosteric modulator 2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix (H) 8, which was predicted by molecular modeling and validated by mutagenesis. According to the model, the nearly planar 1H-imidazo[4,5-c]quinolinamine ring system lies parallel to the transmembrane segments, inserted into an aromatic cage formed by π-π stacking interactions with the side chains of Y2847.55 in TMD7 and Y2938.54 in H8 and by π-NH bonding between Y2847.55 and the exocyclic amine. The 2-cyclohexyl group is positioned "upward" within a small hydrophobic subpocket created by residues in TMDs 1 and 7, while the 3,4-dichlorophenyl group extends toward the lipid interface. An H-bond between the N-1 amine of the heterocycle and the carbonyl of G291.49 further stabilizes the interaction. Molecular dynamics simulations predicted two metastable intermediates, one resembling a pose determined by molecular docking and a second involving transient interactions with Y2938.54; in simulations, each of these intermediates converges into the final bound state. Structure-activity-relationships for replacement of either of the identified exocyclic or endocyclic amines with heteroatoms lacking H-bond donating ability were consistent with the hypothetical pose. Thus, we characterized an allosteric pocket for 1H-imidazo[4,5-c]quinolin-4-amines that is consistent with data generated by orthogonal methods, which will aid in the rational design of improved A3AR positive allosteric modulators. SIGNIFICANCE STATEMENT: Orthosteric A3AR agonists have advanced in clinical trials for inflammatory conditions, liver diseases, and cancer. Thus, the clinical appeal of selective receptor activation could extend to allosteric enhancers, which would induce site- and time-specific activation in the affected tissue. By identifying the allosteric site for known positive allosteric modulators, structure-based drug discovery modalities can be enabled to enhance the pharmacological properties of the 1H-imidazo[4,5-c]quinolin-4-amine class of A3AR positive allosteric modulators.
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Affiliation(s)
- Courtney L Fisher
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
| | - Matteo Pavan
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
| | - Veronica Salmaso
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
| | - Robert F Keyes
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
| | - Tina C Wan
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
| | - Balaram Pradhan
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
| | - Zhan-Guo Gao
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
| | - Brian C Smith
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
| | - Kenneth A Jacobson
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
| | - John A Auchampach
- Departments of Pharmacology & Toxicology and the Cardiovascular Center (C.L.F., T.C.W., J.A.A.) and Biochemistry and the Program in Chemical Biology (R.F.K., B.C.S.), Medical College of Wisconsin, Milwaukee, Wisconsin; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.P., V.S., B.P., Z.-G.G., K.A.J.); and Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (V.S.)
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18
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Nunes EJ, Addy NA, Conn PJ, Foster DJ. Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders. Annu Rev Pharmacol Toxicol 2024; 64:277-289. [PMID: 37552895 PMCID: PMC10841102 DOI: 10.1146/annurev-pharmtox-051921-023858] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.
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Affiliation(s)
- Eric J Nunes
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
| | - Nii A Addy
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Cellular and Molecular Physiology, Interdepartmental Neuroscience Program, and Wu Tsai Institute, Yale University, New Haven, Connecticut, USA
| | - P Jeffrey Conn
- Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA
| | - Daniel J Foster
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, USA;
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19
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Nagori K, Pradhan M, Sharma M, Ajazuddin, Badwaik HR, Nakhate KT. Current Progress on Central Cholinergic Receptors as Therapeutic Targets for Alzheimer's Disease. Curr Alzheimer Res 2024; 21:50-68. [PMID: 38529600 DOI: 10.2174/0115672050306008240321034006] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 03/27/2024]
Abstract
Acetylcholine (ACh) is ubiquitously present in the nervous system and has been involved in the regulation of various brain functions. By modulating synaptic transmission and promoting synaptic plasticity, particularly in the hippocampus and cortex, ACh plays a pivotal role in the regulation of learning and memory. These procognitive actions of ACh are mediated by the neuronal muscarinic and nicotinic cholinergic receptors. The impairment of cholinergic transmission leads to cognitive decline associated with aging and dementia. Therefore, the cholinergic system has been of prime focus when concerned with Alzheimer's disease (AD), the most common cause of dementia. In AD, the extensive destruction of cholinergic neurons occurs by amyloid-β plaques and tau protein-rich neurofibrillary tangles. Amyloid-β also blocks cholinergic receptors and obstructs neuronal signaling. This makes the central cholinergic system an important target for the development of drugs for AD. In fact, centrally acting cholinesterase inhibitors like donepezil and rivastigmine are approved for the treatment of AD, although the outcome is not satisfactory. Therefore, identification of specific subtypes of cholinergic receptors involved in the pathogenesis of AD is essential to develop future drugs. Also, the identification of endogenous rescue mechanisms to the cholinergic system can pave the way for new drug development. In this article, we discussed the neuroanatomy of the central cholinergic system. Further, various subtypes of muscarinic and nicotinic receptors involved in the cognition and pathophysiology of AD are described in detail. The article also reviewed primary neurotransmitters that regulate cognitive processes by modulating basal forebrain cholinergic projection neurons.
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Affiliation(s)
- Kushagra Nagori
- Department of Pharmaceutical Chemistry, Rungta College of Pharmaceutical Sciences and Research, Kurud Road, Kohka, Bhilai 490024, Chhattisgarh, India
| | - Madhulika Pradhan
- Department of Pharmaceutical Technology, Gracious College of Pharmacy, Abhanpur 493661, Chhattisgarh, India
| | - Mukesh Sharma
- Department of Pharmacognosy, Rungta College of Pharmaceutical Sciences and Research, Kurud Road, Kohka, Bhilai 490024, Chhattisgarh, India
| | - Ajazuddin
- Department of Pharmaceutics, Rungta College of Pharmaceutical Sciences and Research, Kurud Road, Kohka, Bhilai 490024, Chhattisgarh, India
| | - Hemant R Badwaik
- Department of Pharmaceutical Chemistry, Shri Shankaracharya Institute of Pharmaceutical Sciences and Research, Junwani, Bhilai 490020, Chhattisgarh, India
| | - Kartik T Nakhate
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule 424001, Maharashtra, India
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20
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Kovyazina IV, Khamidullina AA. Muscarinic Cholinoreceptors in Skeletal Muscle: Localization and Functional Role. Acta Naturae 2023; 15:44-55. [PMID: 38234599 PMCID: PMC10790362 DOI: 10.32607/actanaturae.25259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/24/2023] [Indexed: 01/19/2024] Open
Abstract
The review focuses on the modern concepts of the functions of muscarinic cholinoreceptors in skeletal muscles, particularly, in neuromuscular contacts, and that of the signaling pathways associated with the activation of various subtypes of muscarinic receptors in the skeletal muscles of cold-blooded and warm-blooded animals. Despite the long history of research into the involvement of muscarinic receptors in the modulation of neuromuscular transmission, many aspects of such regulation and the associated intracellular mechanisms remain unclear. Now it is obvious that the functions of muscarinic receptors in skeletal muscle are not limited to the autoregulation of neurosecretion from motor nerve endings but also extend to the development and morphological rearrangements of the synaptic apparatus, coordinating them with the degree of activity. The review discusses various approaches to the study of the functions of muscarinic receptors in motor synapses, as well as the problems arising when interpreting experimental data. The final part of the review is devoted to an analysis of some of the intracellular mechanisms and signaling pathways that mediate the effects of muscarinic agents on neuromuscular transmission.
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Affiliation(s)
- I. V. Kovyazina
- Kazan State Medical University, Kazan, 420012 Russian Federation
- Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, Kazan, 420111 Russian Federation
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21
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Healy D. The past, present and future of anticholinergic drugs. Ther Adv Psychopharmacol 2023; 13:20451253231176375. [PMID: 37701889 PMCID: PMC10493060 DOI: 10.1177/20451253231176375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/28/2023] [Indexed: 09/14/2023] Open
Abstract
In current medical practice, it is difficult to find any reports claiming that drugs that are primarily anticholinergic or those that have significant anticholinergic effects have any therapeutic benefits. These drugs fell into disrepute within the mental health field from the mid-1960s onwards, and their supposed problems extended to elsewhere in medicine after that. There is considerable evidence that this disrepute stemmed more from marketing copy rather than from hard clinical trial data. Many apparent reviews appear to repeat prior claims rather than present substantial or new evidence. This article offers a perspective rather than a systematic review as there is little evidence other than claims to review. The aim is to challenge the conventional narrative that anticholinergic effects are uniquely hazardous by pointing to the uncertain basis for claims about the harms of anticholinergic drugs, antimuscarinic drugs in particular, ending with pointers to recent research that, if realized, might underpin important possible future benefits.
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Affiliation(s)
- David Healy
- Data Based Medicine Americas Ltd., 95 Sandringham Drive, Toronto, ON, M3H 1E1 Canada
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22
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Yamahashi Y, Tsuboi D, Funahashi Y, Kaibuchi K. Neuroproteomic mapping of kinases and their substrates downstream of acetylcholine: finding and implications. Expert Rev Proteomics 2023; 20:291-298. [PMID: 37787112 DOI: 10.1080/14789450.2023.2265067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 08/09/2023] [Indexed: 10/04/2023]
Abstract
INTRODUCTION Since the emergence of the cholinergic hypothesis of Alzheimer's disease (AD), acetylcholine has been viewed as a mediator of learning and memory. Donepezil improves AD-associated learning deficits and memory loss by recovering brain acetylcholine levels. However, it is associated with side effects due to global activation of acetylcholine receptors. Muscarinic acetylcholine receptor M1 (M1R), a key mediator of learning and memory, has been an alternative target. The importance of targeting a specific pathway downstream of M1R has recently been recognized. Elucidating signaling pathways beyond M1R that lead to learning and memory holds important clues for AD therapeutic strategies. AREAS COVERED This review first summarizes the role of acetylcholine in aversive learning, one of the outputs used for preliminary AD drug screening. It then describes the phosphoproteomic approach focused on identifying acetylcholine intracellular signaling pathways leading to aversive learning. Finally, the intracellular mechanism of donepezil and its effect on learning and memory is discussed. EXPERT OPINION The elucidation of signaling pathways beyond M1R by phosphoproteomic approach offers a platform for understanding the intracellular mechanism of AD drugs and for developing AD therapeutic strategies. Clarifying the molecular mechanism that links the identified acetylcholine signaling to AD pathophysiology will advance the development of AD therapeutic strategies.
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Affiliation(s)
- Yukie Yamahashi
- Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi, Japan
| | - Daisuke Tsuboi
- Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi, Japan
| | - Yasuhiro Funahashi
- Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi, Japan
| | - Kozo Kaibuchi
- Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Aichi, Japan
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23
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Dean B. Muscarinic M1 and M4 receptor agonists for schizophrenia: promising candidates for the therapeutic arsenal. Expert Opin Investig Drugs 2023; 32:1113-1121. [PMID: 37994870 DOI: 10.1080/13543784.2023.2288074] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 11/22/2023] [Indexed: 11/24/2023]
Abstract
INTRODUCTION Successful phase 3 trials of KarXT in people with schizophrenia herald a new era of treating the disorder with drugs that do not target the dopamine D2 receptor. The active component of KarXT is xanomeline, a muscarinic (CHRM) M1 and M4 agonist, making muscarinic receptors a viable target for treating schizophrenia. AREAS COVERED This review covers the process of taking drugs that activate the muscarinic M1 and M4 receptors from conceptualization to the clinic and details the mechanisms by which activating the CHRM1 and 4 can affect the broad spectrum of symptoms experienced by people with schizophrenia. EXPERT OPINION Schizophrenia is a syndrome which means drugs that activate muscarinic M1 and M4 receptors, as was the case for antipsychotic drugs acting on the dopamine D2 receptor, will not give optimal outcomes in everyone within the syndrome. Thus, it would be ideal to identify people who are responsive to drugs activating the CHRM1 and 4. Given knowledge of the actions of these receptors, it is possible treatment non-response could be restricted to sub-groups within the syndrome who have deficits in cortical CHRM1 or those with one of the cognitive endophenotypes that may be identifiable by changes in the blood transcriptome.
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Affiliation(s)
- Brian Dean
- The Synaptic Biology and Cognition Laboratory, The Florey, Parkville, Victoria, Australia
- Florey Department of Neuroscience and Mental Health, Parkville, Victoria, Australia
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24
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Meyer JM, Correll CU. Increased Metabolic Potential, Efficacy, and Safety of Emerging Treatments in Schizophrenia. CNS Drugs 2023; 37:545-570. [PMID: 37470979 PMCID: PMC10374807 DOI: 10.1007/s40263-023-01022-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 07/21/2023]
Abstract
Patients with schizophrenia experience a broad range of detrimental health outcomes resulting from illness severity, heterogeneity of disease, lifestyle behaviors, and adverse effects of antipsychotics. Because of these various factors, patients with schizophrenia have a much higher risk of cardiometabolic abnormalities than people without psychiatric illness. Although exposure to many antipsychotics increases cardiometabolic risk factors, mortality is higher in patients who are not treated versus those who are treated with antipsychotics. This indicates both direct and indirect benefits of adequately treated illness, as well as the need for beneficial medications that result in fewer cardiometabolic risk factors and comorbidities. The aim of the current narrative review was to outline the association between cardiometabolic dysfunction and schizophrenia, as well as discuss the confluence of factors that increase cardiometabolic risk in this patient population. An increased understanding of the pathophysiology of schizophrenia has guided discovery of novel treatments that do not directly target dopamine and that not only do not add, but may potentially minimize relevant cardiometabolic burden for these patients. Key discoveries that have advanced the understanding of the neural circuitry and pathophysiology of schizophrenia now provide possible pathways toward the development of new and effective treatments that may mitigate the risk of metabolic dysfunction in these patients. Novel targets and preclinical and clinical data on emerging treatments, such as glycine transport inhibitors, nicotinic and muscarinic receptor agonists, and trace amine-associated receptor-1 agonists, offer promise toward relevant therapeutic advancements. Numerous areas of investigation currently exist with the potential to considerably progress our knowledge and treatment of schizophrenia.
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Affiliation(s)
- Jonathan M Meyer
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
| | - Christoph U Correll
- Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA
- Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany
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25
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Xu R, Wan M, Shi X, Ma S, Zhang L, Yi P, Zhang R. A Rab10-ACAP1-Arf6 GTPases cascade modulates M4 muscarinic acetylcholine receptor trafficking and signaling. Cell Mol Life Sci 2023; 80:87. [PMID: 36917255 PMCID: PMC11072986 DOI: 10.1007/s00018-023-04722-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/06/2023] [Accepted: 02/08/2023] [Indexed: 03/16/2023]
Abstract
Membrane trafficking processes regulate the G protein-coupled receptor activity. The muscarinic acetylcholine receptors (mAChRs) are highly pursued drug targets for neurological diseases, but the cellular machineries that control the trafficking of these receptors remain largely elusive. Here, we revealed the role of the small GTPase Rab10 as a negative regulator for the post-activation trafficking of M4 mAChR and the underlying mechanism. We show that constitutively active Rab10 arrests the receptor within Rab5-positive early endosomes and significantly hinders the resensitization of M4-mediated Ca2+ signaling. Mechanistically, M4 binds to Rab10-GTP, which requires the motif 386RKKRQMAA393 (R386-A393) within the third intracellular loop. Moreover, Rab10-GTP inactivates Arf6 by recruiting the Arf6 GTPase-activating protein, ACAP1. Strikingly, deletion of the motif R386-A393 causes M4 to bypass the control by Rab10 and switch to the Rab4-facilitated fast recycling pathway, thus reusing the receptor. Therefore, Rab10 couples the cargo sorting and membrane trafficking regulation through cycle between GTP-bound and GDP-bound state. Our findings suggest a model that Rab10 binds to the M4 like a molecular brake and controls the receptor's transport through endosomes, thus modulating the signaling, and this regulation is specific among the mAChR subtypes.
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Affiliation(s)
- Rongmei Xu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Min Wan
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, USA
| | - Xuemeng Shi
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
- College of Life Science, Henan Agricultural University, Zhengzhou, Henan, China
| | - Shumin Ma
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lina Zhang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ping Yi
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Rongying Zhang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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26
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Wang J, Cui ZJ. Photodynamic Activation of Cholecystokinin 1 Receptor Is Conserved in Mammalian and Avian Pancreatic Acini. Biomedicines 2023. [DOI: https:/doi.org/10.3390/biomedicines11030885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2023] Open
Abstract
Cholecystokinin 1 receptor (CCK1R) is the only G protein coupled receptor that is activated in type II photodynamic action, but whether this is a property common to both mammalian and avian species is not known. In this work, pancreatic acini were isolated from the rat, mouse, and Peking duck, and photodynamic CCK1R activation was examined. Isolated pancreatic acini were exposed to photosensitizer sulphonated aluminum phthalocyanine (SALPC) and photodynamic action elicited by a brief light-emitting diode (LED 675 nm) pulse (1.5 min); photodynamic CCK1R activation was assessed by Fura-2 fluorescent calcium imaging. Photodynamic action was found to induce persistent calcium oscillations in rat, mouse, and Peking duck pancreatic acini, with the sensitivity order of mouse > rat > Peking duck. Photodynamically-activated CCK1R could be inhibited reversibly by CCK1R antagonist devazepide (1 μM); photodynamic CCK1R activation was blocked by pre-incubation with 1O2 quencher Trolox C (300 µM). The sensitivity of photodynamic CCK1R activation was correlated with the increasing size of the disordered region in intracellular loop 3. These data suggest that photodynamic CCK1R activation is conserved in both mammalian and avian species, as evidenced by the presence of the photodynamic activation motif “YFM” in transmembrane domain 3.
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Affiliation(s)
- Jie Wang
- Institute of Cell Biology, Beijing Normal University, Beijing 100875, China
| | - Zong Jie Cui
- Institute of Cell Biology, Beijing Normal University, Beijing 100875, China
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27
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Wang J, Cui ZJ. Photodynamic Activation of Cholecystokinin 1 Receptor Is Conserved in Mammalian and Avian Pancreatic Acini. Biomedicines 2023; 11:885. [PMID: 36979864 PMCID: PMC10046250 DOI: 10.3390/biomedicines11030885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 03/08/2023] [Accepted: 03/08/2023] [Indexed: 03/18/2023] Open
Abstract
Cholecystokinin 1 receptor (CCK1R) is the only G protein coupled receptor that is activated in type II photodynamic action, but whether this is a property common to both mammalian and avian species is not known. In this work, pancreatic acini were isolated from the rat, mouse, and Peking duck, and photodynamic CCK1R activation was examined. Isolated pancreatic acini were exposed to photosensitizer sulphonated aluminum phthalocyanine (SALPC) and photodynamic action elicited by a brief light-emitting diode (LED 675 nm) pulse (1.5 min); photodynamic CCK1R activation was assessed by Fura-2 fluorescent calcium imaging. Photodynamic action was found to induce persistent calcium oscillations in rat, mouse, and Peking duck pancreatic acini, with the sensitivity order of mouse > rat > Peking duck. Photodynamically-activated CCK1R could be inhibited reversibly by CCK1R antagonist devazepide (1 μM); photodynamic CCK1R activation was blocked by pre-incubation with 1O2 quencher Trolox C (300 µM). The sensitivity of photodynamic CCK1R activation was correlated with the increasing size of the disordered region in intracellular loop 3. These data suggest that photodynamic CCK1R activation is conserved in both mammalian and avian species, as evidenced by the presence of the photodynamic activation motif "YFM" in transmembrane domain 3.
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Affiliation(s)
| | - Zong Jie Cui
- Institute of Cell Biology, Beijing Normal University, Beijing 100875, China;
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28
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Dean B, Bakker G, Ueda HR, Tobin AB, Brown A, Kanaan RAA. A growing understanding of the role of muscarinic receptors in the molecular pathology and treatment of schizophrenia. Front Cell Neurosci 2023; 17:1124333. [PMID: 36909280 PMCID: PMC9992992 DOI: 10.3389/fncel.2023.1124333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/06/2023] [Indexed: 02/24/2023] Open
Abstract
Pre-clinical models, postmortem and neuroimaging studies all support a role for muscarinic receptors in the molecular pathology of schizophrenia. From these data it was proposed that activation of the muscarinic M1 and/or M4 receptor would reduce the severity of the symptoms of schizophrenia. This hypothesis is now supported by results from two clinical trials which indicate that activating central muscarinic M1 and M4 receptors can reduce the severity of positive, negative and cognitive symptoms of the disorder. This review will provide an update on a growing body of evidence that argues the muscarinic M1 and M4 receptors have critical roles in CNS functions that are dysregulated by the pathophysiology of schizophrenia. This realization has been made possible, in part, by the growing ability to visualize and quantify muscarinic M1 and M4 receptors in the human CNS using molecular neuroimaging. We will discuss how these advances have provided evidence to support the notion that there is a sub-group of patients within the syndrome of schizophrenia that have a unique molecular pathology driven by a marked loss of muscarinic M1 receptors. This review is timely, as drugs targeting muscarinic receptors approach clinical use for the treatment of schizophrenia and here we outline the background biology that supported development of such drugs to treat the disorder.
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Affiliation(s)
- Brian Dean
- Synaptic Biology and Cognition Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
| | | | - Hiroki R Ueda
- Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Laboratory for Synthetic Biology, RIKEN Center for Biosystems Dynamics Research, Osaka, Japan
| | - Andrew B Tobin
- Advanced Research Centre (ARC), School of Molecular Bioscience, University of Glasgow, Glasgow, United Kingdom
| | | | - Richard A A Kanaan
- Department of Psychiatry, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia
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29
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Kurose H. [Biased Signaling through G Protein-coupled Receptors]. YAKUGAKU ZASSHI 2022; 142:1091-1101. [PMID: 36184444 DOI: 10.1248/yakushi.22-00087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It is well-established that G protein-coupled receptors (GPCRs) transduce signals into cells using G proteins as intermediary molecules. β-Arrestins are molecules involved in regulating GPCRs; however, it has recently been reported that β-arrestins can also mediate signaling through GPCRs. Signaling through G proteins or β-arrestins can be activated selectively using specific agonists; of the latter, those that can selectively activate either G proteins or β-arrestins are called biased agonists. The clinical use of biased agonists could potentially induce fewer side effects. However, partial agonists can also explain the mechanism of G protein-biased agonists; thus, appropriate assay systems must be considered. Endogenous agonists are known to bind to orthosteric and allosteric sites in the agonist binding site, and the allosteric site is associated with the activity of biased agonists. This current review presents a detailed discussion of biased agonists.
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Affiliation(s)
- Hitoshi Kurose
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University
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30
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Sabbir MG, Speth RC, Albensi BC. Loss of Cholinergic Receptor Muscarinic 1 (CHRM1) Protein in the Hippocampus and Temporal Cortex of a Subset of Individuals with Alzheimer’s Disease, Parkinson’s Disease, or Frontotemporal Dementia: Implications for Patient Survival. J Alzheimers Dis 2022; 90:727-747. [DOI: 10.3233/jad-220766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: Dysfunction of cholinergic neurotransmission is a hallmark of Alzheimer’s disease (AD); forming the basis for using acetylcholine (ACh) esterase (AChE) inhibitors to mitigate symptoms of ACh deficiency in AD. The Cholinergic Receptor Muscarinic 1 (CHRM1) is highly expressed in brain regions impaired by AD. Previous analyses of postmortem AD brains revealed unaltered CHRM1 mRNA expression compared to normal brains. However, the CHRM1 protein level in AD and other forms of dementia has not been extensively studied. Reduced expression of CHRM1 in AD patients may explain the limited clinical efficacy of AChE inhibitors. Objective: To quantify CHRM1 protein in the postmortem hippocampus and temporal cortex of AD, Parkinson’s disease (PD), and frontotemporal dementia (FTD) patients. Methods: Western blotting was performed on postmortem hippocampus (N = 19/73/7/9: unaffected/AD/FTD/PD) and temporal cortex (N = 9/74/27: unaffected/AD/PD) using a validated anti-CHRM1 antibody. Results: Quantification based on immunoblotting using a validated anti-CHRM1 antibody revealed a significant loss of CHRM1 protein level (<50%) in the hippocampi (78% AD, 66% PD, and 85% FTD) and temporal cortices (56% AD and 42% PD) of dementia patients. Loss of CHRM1 in the temporal cortex was significantly associated with early death (<65–75 years) for both AD and PD patients. Conclusion: Severe reduction of CHRM1 in a subset of AD and PD patients can explain the reported low efficacy of AChE inhibitors as a mitigating treatment for dementia patients. Based on this study, it can be suggested that future research should prioritize therapeutic restoration of CHRM1 protein levels in cholinergic neurons.
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Affiliation(s)
- Mohammad Golam Sabbir
- Alzo Biosciences Inc., San Diego, CA, USA
- St. Boniface Hospital Albrechtsen Research Centre, Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Manitoba, Canada
- Nova Southeastern University, College of Pharmacy, Davie, FL, USA
| | - Robert C. Speth
- Nova Southeastern University, College of Pharmacy, Davie, FL, USA
- Department of Pharmacology and Physiology, School of Medicine, Georgetown University, Washington, DC, USA
| | - Benedict C. Albensi
- Nova Southeastern University, College of Pharmacy, Davie, FL, USA
- St. Boniface Hospital Albrechtsen Research Centre, Division of Neurodegenerative Disorders, Winnipeg, Manitoba, Canada
- University of Manitoba, College of Medicine, Winnipeg, Manitoba, Canada
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Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC. Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia. Am J Psychiatry 2022; 179:611-627. [PMID: 35758639 DOI: 10.1176/appi.ajp.21101083] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Schizophrenia remains a challenging disease to treat effectively with current antipsychotic medications due to their limited efficacy across the entire spectrum of core symptoms as well as their often burdensome side-effect profiles and poor tolerability. An unmet need remains for novel, mechanistically unique, and better tolerated therapeutic agents for treating schizophrenia, especially those that treat not only positive symptoms but also the negative and cognitive symptoms of the disease. Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia. These unexpected clinical findings have prompted considerable efforts across academia and industry to target mAChRs as a new approach to potentially treat schizophrenia and other psychotic disorders. The authors discuss recent advances in mAChR biology and pharmacology and the current understanding of the relative roles of the various mAChR subtypes, their downstream cellular effectors, and key neural circuits mediating the reduction in the core symptoms of schizophrenia in patients treated with xanomeline. They also provide an update on the status of novel mAChR agonists currently in development for potential treatment of schizophrenia and other neuropsychiatric disorders.
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Abstract
Agonists are defined as the ligands that activate intracellular signaling and evoke cellular responses. Synthetic and endogenous agonists should bind specific amino acids to activate G protein-coupled receptor (GPCR). Agonists that induce maximal responses are full agonists. Partial agonists cannot induce full responses unlike full agonists. In definition, antagonists inhibit agonist-stimulated responses by binding to orthosteric or allosteric sites. Antagonists modulate agonist-induced responses and are often related with inverse agonist activity. However, the relationship between antagonists and partial agonists is complex. An antagonist behaves as a partial agonist when the constitutive activity of the GPCR is high. In contrast, a partial agonist with very weak intrinsic activity may be classified as an antagonist. Thus, antagonisms of the compounds are influenced by constitutive activity of GPCRs, intrinsic activity and differences in the binding sites of GPCRs. Since "antagonism" has been revealed to have multiple aspects and more complex than previously thought, it may be difficult to classify each compound as simply "agonist" or "antagonist" as before. In this review, we discuss the recent findings and perspectives on the pharmacology of GPCR-binding antagonists, inverse agonists, and signaling.
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Affiliation(s)
- Hitoshi Kurose
- Department of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu University
| | - Sang Geon Kim
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul
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Zlotos DP, Mandour YM, Jensen AA. Strychnine and its mono- and dimeric analogues: a pharmaco-chemical perspective. Nat Prod Rep 2022; 39:1910-1937. [PMID: 35380133 DOI: 10.1039/d1np00079a] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Covering: up to November 2021Since its isolation in 1818, strychnine has attracted the attention of a plethora of chemists and pharmacologists who have established its structure, developed total syntheses, and examined its complex pharmacology. While numerous reviews on structure elucidation and total synthesis of strychnine are available, reports on structure-activity relationships (SARs) of this fascinating alkaloid are rare. In this review, we present and discuss structures, synthetic approaches, metabolic transformations, and the diverse pharmacological actions of strychnine and its mono- and dimeric analogues. Particular attention is given to its SARs at glycine receptors (GlyRs) in light of recently published high-resolution structures of strychnine-GlyR complexes. Other pharmacological actions of strychnine and its derivatives, such as their antagonistic properties at nicotinic acetylcholine receptors (nAChRs), allosteric modulation of muscarinic acetylcholine receptors as well as anti-cancer and anti-plasmodial effects are also critically reviewed, and possible future developments in the field are discussed.
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Affiliation(s)
- Darius P Zlotos
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, New Cairo City, 11835 Cairo, Egypt.
| | - Yasmine M Mandour
- School of Life and Medical Sciences, University of Hertfordshire hosted by Global Academic Foundation, New Administrative Capital, Cairo, Egypt
| | - Anders A Jensen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark
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Dwomoh L, Tejeda G, Tobin A. Targeting the M1 muscarinic acetylcholine receptor in Alzheimer's disease. Neuronal Signal 2022; 6:NS20210004. [PMID: 35571495 PMCID: PMC9069568 DOI: 10.1042/ns20210004] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/01/2022] [Accepted: 04/04/2022] [Indexed: 11/17/2022] Open
Abstract
Alzheimer's disease (AD) remains a major cause of morbidity and mortality worldwide, and despite extensive research, only a few drugs are available for management of the disease. One strategy has been to up-regulate cholinergic neurotransmission to improve cognitive function, but this approach has dose-limiting adverse effects. To avoid these adverse effects, new drugs that target specific receptor subtypes of the cholinergic system are needed, and the M1 subtype of muscarinic acetylcholine receptor (M1-mAChR) has been shown to be a good target for this approach. By using several strategies, M1-mAChR ligands have been developed and trialled in preclinical animal models and in human studies, with varying degrees of success. This article reviews the different approaches to targeting the M1-mAChR in AD and discusses the advantages and limitations of these strategies. The factors to consider in targeting the M1-mAChR in AD are also discussed.
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Affiliation(s)
- Louis Dwomoh
- The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Gonzalo S. Tejeda
- The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Andrew B. Tobin
- The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M1 Antagonists. Pharmaceuticals (Basel) 2022; 15:ph15020248. [PMID: 35215360 PMCID: PMC8879200 DOI: 10.3390/ph15020248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/05/2022] [Accepted: 02/14/2022] [Indexed: 11/17/2022] Open
Abstract
Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have identified a series of twelve 4,4’-difluorobenzhydrol carbamates through a rigorous docking campaign leveraging commercially available amine databases. After synthesis, these compounds have been evaluated for their physico–chemical property profiles, including characteristics such as HPLC-logD, tPSA, logBB, and logPS. For all the synthesized carbamates, these characteristics indicate the potential for BBB permeation. In competitive radioligand binding experiments using Chinese hamster ovary cell membranes expressing the individual human mAChR subtype hM1-hM5, the most promising compound 2 displayed a high binding affinitiy towards hM1R (1.2 nM) while exhibiting modest-to-excellent selectivity versus the hM2-5R (4–189-fold). All 12 compounds were shown to act in an antagonistic fashion towards hM1R using a dose-dependent calcium mobilization assay. The structural eligibility for radiolabeling and their pharmacological and physico–chemical property profiles render compounds 2, 5, and 7 promising candidates for future position emission tomography (PET) tracer development.
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Biased M1 muscarinic receptor mutant mice show accelerated progression of prion neurodegenerative disease. Proc Natl Acad Sci U S A 2021; 118:2107389118. [PMID: 34893539 PMCID: PMC8685681 DOI: 10.1073/pnas.2107389118] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2021] [Indexed: 01/14/2023] Open
Abstract
The M1 muscarinic acetylcholine receptor (M1-receptor) plays a crucial role in learning and memory and is a validated drug target for the treatment of Alzheimer’s disease (AD). Furthermore, M1-receptor ligands have been demonstrated to display disease-modifying effects in preclinical models of neurodegenerative disease. By employing a genetic mouse model expressing a G protein–biased M1-receptor in combination with a mouse model of terminal neurodegenerative disease, we demonstrate here that the M1-receptor exerts an inherent neuroprotective activity that is dependent on its phosphorylation status. Thus, in AD drug development programs, M1-receptor ligands that maintain the receptor phosphorylation status will be more likely to lead to beneficial neuroprotective outcomes. There are currently no treatments that can slow the progression of neurodegenerative diseases, such as Alzheimer’s disease (AD). There is, however, a growing body of evidence that activation of the M1 muscarinic acetylcholine receptor (M1-receptor) can not only restore memory loss in AD patients but in preclinical animal models can also slow neurodegenerative disease progression. The generation of an effective medicine targeting the M1-receptor has however been severely hampered by associated cholinergic adverse responses. By using genetically engineered mouse models that express a G protein–biased M1-receptor, we recently established that M1-receptor mediated adverse responses can be minimized by ensuring activating ligands maintain receptor phosphorylation/arrestin-dependent signaling. Here, we use these same genetic models in concert with murine prion disease, a terminal neurodegenerative disease showing key hallmarks of AD, to establish that phosphorylation/arrestin-dependent signaling delivers neuroprotection that both extends normal animal behavior and prolongs the life span of prion-diseased mice. Our data point to an important neuroprotective property inherent to the M1-receptor and indicate that next generation M1-receptor ligands designed to drive receptor phosphorylation/arrestin-dependent signaling would potentially show low adverse responses while delivering neuroprotection that will slow disease progression.
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Schledwitz A, Sundel MH, Alizadeh M, Hu S, Xie G, Raufman JP. Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer. Int J Mol Sci 2021; 22:ijms222313153. [PMID: 34884958 PMCID: PMC8658119 DOI: 10.3390/ijms222313153] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/01/2021] [Accepted: 12/02/2021] [Indexed: 12/17/2022] Open
Abstract
Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers.
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Affiliation(s)
- Alyssa Schledwitz
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.S.); (M.A.); (S.H.); (G.X.)
| | - Margaret H. Sundel
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Madeline Alizadeh
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.S.); (M.A.); (S.H.); (G.X.)
- The Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Shien Hu
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.S.); (M.A.); (S.H.); (G.X.)
- VA Maryland Healthcare System, Baltimore, MD 21201, USA
| | - Guofeng Xie
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.S.); (M.A.); (S.H.); (G.X.)
- VA Maryland Healthcare System, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.S.); (M.A.); (S.H.); (G.X.)
- VA Maryland Healthcare System, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Correspondence: ; Tel.: +1-410-328-8728
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Neuropharmacology of Cevimeline and Muscarinic Drugs-Focus on Cognition and Neurodegeneration. Int J Mol Sci 2021; 22:ijms22168908. [PMID: 34445613 PMCID: PMC8396258 DOI: 10.3390/ijms22168908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/18/2022] Open
Abstract
At present, Alzheimer’s disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-β (Aβ) peptide in the cerebral spinal fluid of Alzheimer’s patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.
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Soma S, Suematsu N, Sato AY, Tsunoda K, Bramian A, Reddy A, Takabatake K, Karube F, Fujiyama F, Shimegi S. Acetylcholine from the nucleus basalis magnocellularis facilitates the retrieval of well-established memory. Neurobiol Learn Mem 2021; 183:107484. [PMID: 34175450 DOI: 10.1016/j.nlm.2021.107484] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/14/2021] [Accepted: 06/22/2021] [Indexed: 01/31/2023]
Abstract
Retrieval deficit of long-term memory is a cardinal symptom of dementia and has been proposed to associate with abnormalities in the central cholinergic system. Difficulty in the retrieval of memory is experienced by healthy individuals and not limited to patients with neurological disorders that result in forgetfulness. The difficulty of retrieving memories is associated with various factors, such as how often the event was experienced or remembered, but it is unclear how the cholinergic system plays a role in the retrieval of memory formed by a daily routine (accumulated experience). To investigate this point, we trained rats moderately (for a week) or extensively (for a month) to detect a visual cue in a two-alternative forced-choice task. First, we confirmed the well-established memory in the extensively trained group was more resistant to the retrieval problem than recently acquired memory in the moderately trained group. Next, we tested the effect of a cholinesterase inhibitor, donepezil, on the retrieval of memory after a long no-task period in extensively trained rats. Pre-administration of donepezil improved performance and reduced the latency of task initiation compared to the saline-treated group. Finally, we lesioned cholinergic neurons of the nucleus basalis magnocellularis (NBM), which project to the entire neocortex, by injecting the cholinergic toxin 192 IgG-saporin. NBM-lesioned rats showed severely impaired task initiation and performance. These abilities recovered as the trials progressed, though they never reached the level observed in rats with intact NBM. These results suggest that acetylcholine released from the NBM contributes to the retrieval of well-established memory developed by a daily routine.
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Affiliation(s)
- Shogo Soma
- Graduate School of Medicine, Osaka University, Osaka 560-0043, Japan; Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA; Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
| | - Naofumi Suematsu
- Graduate School of Medicine, Osaka University, Osaka 560-0043, Japan; Center for Sciences Towards Symbiosis Among Human, Machine and Data, Kyoto Sangyo University, Kyoto 603-8555, Japan
| | - Akinori Y Sato
- Graduate School of Medicine, Osaka University, Osaka 560-0043, Japan; Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan
| | - Keisuke Tsunoda
- Graduate School of Medicine, Osaka University, Osaka 560-0043, Japan
| | - Allen Bramian
- Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA
| | - Anish Reddy
- Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, USA
| | - Koki Takabatake
- College of Arts & Sciences, Washington University in Saint Louis, Saint Louis, MO 63130, USA
| | - Fuyuki Karube
- Graduate School of Brain Science, Doshisha University, Kyoto 619-0225, Japan; Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Fumino Fujiyama
- Graduate School of Brain Science, Doshisha University, Kyoto 619-0225, Japan; Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Satoshi Shimegi
- Graduate School of Medicine, Osaka University, Osaka 560-0043, Japan; Center for Education in Liberal Arts and Sciences, Osaka University, Toyonaka, Osaka 560-0043, Japan.
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