Article
Chemistry, Medicinal
Manuela Jorg, Emma T. van der Westhuizen, Yao Lu, K. H. Christopher Choy, David M. Shackleford, Elham Khajehali, Andrew B. Tobin, David M. Thal, Ben Capuano, Arthur Christopoulos, Celine Valant, Peter J. Scammells
Summary: The synthesis and comprehensive pharmacological evaluation of M4 mAChR PAMs structurally related to 1e, Me-C-c, [11C]MK-6884 and [18F]12 were reported. Small structural changes to the PAMs resulted in significant differences in baseline, potency, and maximum effect measures in cAMP assays compared to the endogenous ligand acetylcholine (ACh). The discovery of novel PAMs with improved allosteric properties, 6k and 6l, and their ability to cross the blood-brain barrier make them more suitable for future preclinical assessment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Manuela Jorg, Elham Khajehali, Emma T. van der Westhuizen, K. H. C. Choy, David M. Shackleford, Andrew B. Tobin, Patrick M. Sexton, Celine Valant, Ben Capuano, Arthur Christopoulos, Peter J. Scammells
Summary: This study investigated the structure-activity relationships of 4-phenylpyridin-2-one and 6-phenylpyrimidin-4-one M(1)muscarinic acetylcholine receptor positive allosteric modulators (PAMs), showing that modifications to the analogues result in nuanced effects on the allosteric properties. The research also found that despite primarily acting as affinity modulators, the PAMs displayed different pharmacological properties across the two cellular assays. The novel PAM7 was identified as a potential lead candidate for further development due to its lower BBB permeability and improved exposure in the periphery compared to lead2.
Article
Multidisciplinary Sciences
Mihoko Kato, Irina Kolotuev, Alexandre Cunha, Shahla Gharib, Paul W. Sternberg
Summary: This study reveals the function of muscarinic receptor GAR-3 in epithelial cell migration in C. elegans, including receiving signals from cholinergic neurons, affecting migratory path, and determining migration direction. The experimental results suggest that the regulation of GAR-3 receptor in LC is accomplished by specific downstream signaling pathways, and there is a clear correlation between GAR-3 receptor activation level and LC migration direction.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Medicinal
Paul K. Spearing, Hyekyung P. Cho, Vincent B. Luscombe, Anna L. Blobaum, Olivier Boutaud, Darren W. Engers, Alice L. Rodriguez, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Aaron M. Bender
Summary: This letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) for the muscarinic acetylcholine receptor M-1 (mAChR M-1). Through continued optimization, two compounds, 8b (VU6005610) and 20a (VU6005852), were found to have robust selectivity for the M-1 mAChR with no agonism. Additionally, compound 8b showed high brain exposure in a rodent IV cassette model.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Wessel A. C. Burger, Patrick R. Gentry, Alice E. Berizzi, Ziva Vuckovic, Emma T. van der Westhuizen, Geoff Thompson, Mahmuda Yeasmin, Craig W. Lindsley, Patrick M. Sexton, Christopher J. Langmead, Andrew B. Tobin, Arthur Christopoulos, Celine Valant, David M. Thal
Summary: The potential binding site for ML375 in M-5 mAChR was identified at the interface of TMs 2-4, aiding in the development of novel selective M-5 mAChR modulators.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Multidisciplinary Sciences
Wessel A. C. Burger, Vi Pham, Ziva Vuckovic, Alexander S. Powers, Jesse I. Mobbs, Yianni Laloudakis, Alisa Glukhova, Denise Wootten, Andrew B. Tobin, Patrick M. Sexton, Steven M. Paul, Christian C. Felder, Radostin Danev, Ron O. Dror, Arthur Christopoulos, Celine Valant, David M. Thal
Summary: The M4 muscarinic acetylcholine receptor is a significant drug target for the treatment of psychosis, cognition, and addiction. The clinical trial of xanomeline has shown promise in improving symptoms and the cryo-EM structure reveals the binding mechanism, providing insight into its complex pharmacology.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Dongxue Wang, Yunjin Yao, Shiqi Wang, Yifei Hou, Lanxue Zhao, Hao Wang, Hongzhuan Chen, Jianrong Xu
Summary: In this study, we compared the efficacy of six agonists in inducing the recruitment of G proportional to q and beta-arrestin2 to M1mAChR using BRET assays. Our findings reveal significant variations in agonist efficacy for the recruitment of G proportional to q and beta-arrestin2. By characterizing bias towards G proportional to q and beta-arrestin2 recruitment, our study provides insights into M1mAChR signaling bias.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Ee Von Moo, Jeffrey R. van Senten, Hans Brauner-Osborne, Thor C. Moller
Summary: This article discusses the importance of agonist-induced endocytosis in regulating cell surface receptor density and signaling. While arrestins are key regulators in GPCR internalization, there are also independent endocytosis pathways for GPCRs, expanding the diversity of the process.
MOLECULAR PHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Madeline F. Long, Rory A. Capstick, Paul K. Spearing, Julie L. Engers, Alison R. Gregro, Sean R. Bollinger, Sichen Chang, Vincent B. Luscombe, Alice L. Rodriguez, Hyekyung P. Cho, Colleen M. Niswender, Thomas M. Bridges, P. Jeffrey Conn, Craig W. Lindsley, Darren W. Engers, Kayla J. Temple
Summary: The Letter details efforts to develop novel tricyclic M-4 PAM scaffolds with improved pharmacological properties. A tie-back strategy was employed to replace the core structure, leading to the discovery of two novel tricyclic cores with low nanomolar potency against the human M-4 receptor.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Review
Chemistry, Medicinal
Edouard Montigne, David Balayssac
Summary: This scoping review provides an overview of studies on peripheral neuropathic pain (PNP) in rodent models, exploring compounds targeting cholinergic neurotransmission. The results highlight the potential of cholinergic compounds for the management of neuropathic pain, emphasizing the need for clinical trials.
Review
Pharmacology & Pharmacy
Huong T. M. Nguyen, Emma T. van der Westhuizen, Christopher J. Langmead, Andrew B. Tobin, Patrick M. Sexton, Arthur Christopoulos, Celine Valant
Summary: This review focuses on the drug discovery of M-1 receptor for the treatment of Alzheimer's disease and schizophrenia. Despite some progress, only a few drugs have reached clinical trials due to cholinergic adverse effects.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biotechnology & Applied Microbiology
Wei Yang, Lijuan He
Summary: Hederagenin (HE) plays a protective role in inhibiting cell proliferation and improving fibrosis. The study reveals that HE protects against renal fibrosis by targeting the Muscarinic acetylcholine receptor M3.
Article
Neurosciences
Eva Dolejsi, Eszter Szanti-Pinter, Nikolai Chetverikov, Dominik Nelic, Alena Randakova, Vladimir Dolezal, Eva Kudova, Jan Jakubik
Summary: The study revealed that membrane cholesterol can modulate the function of muscarinic receptors, with different steroidal compounds showing varying affinity for the receptors. Corticosterone and progesterone were found to allosterically modulate receptor function under physiological conditions.
Article
Pharmacology & Pharmacy
Victoria R. Sanders, Neil S. Millar
Summary: Considerable progress has been made in the identification and characterization of subtype-selective modulators of nicotinic acetylcholine receptors (nAChRs), specifically alpha 7 nAChRs. This review focuses on alpha 7-selective modulators that bind to receptor sites other than the orthosteric agonist binding site for acetylcholine. The mechanism of action and binding sites of these modulators is still a topic of debate.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Multidisciplinary Sciences
Miriam Scarpa, Colin Molloy, Laura Jenkins, Bethany Strellis, Rebecca F. Budgett, Sarah Hesse, Louis Dwomoh, Sara Marsango, Gonzalo S. Tejeda, Mario Rossi, Zeshan Ahmed, Graeme Milligan, Brian D. Hudson, Andrew B. Tobin, Sophie J. Bradley
Summary: Current treatments for neurodegenerative diseases like Alzheimer's disease have shown limited effectiveness, but activating the M1 receptor could potentially restore memory and slow disease progression. Recent research suggests that minimizing adverse reactions associated with M1 receptor activation can be achieved by ensuring proper phosphorylation and arrestin-dependent signaling. This approach shows promise for developing next-generation M1 receptor ligands with reduced side effects and improved neuroprotection.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Geriatrics & Gerontology
Antoine Hone-Blanchet, Anastasia Bohsali, Lisa C. Krishnamurthy, Salman Shahid, Qixiang Lin, Liping Zhao, David Loring, Felicia Goldstein, Samantha E. John, Candace C. Fleischer, Allan Levey, James Lah, Deqiang Qiu, Bruce Crosson
Summary: The elevated expression of beta-amyloid and tau are considered risk factors for Alzheimer's disease. This study found that levels of frontal GABA+ and mI/tCr are influenced by age, with GABA+ levels decreasing with age and the opposite for mI/tCr.
NEUROBIOLOGY OF AGING
(2022)
Article
Psychology, Developmental
Samantha E. John, Sarah A. Evans, Bona Kim, Petek Ozgul, David W. Loring, Monica Parker, James J. Lah, Allan I. Levey, Felicia C. Goldstein
Summary: The study found that differences in performance on cognitive tests using mobile applications were not significant between Black and non-Hispanic white participants. Both groups found the app-based measures feasible and acceptable, with Black participants showing a stronger likelihood of future use.
AGING NEUROPSYCHOLOGY AND COGNITION
(2022)
Article
Clinical Neurology
Allan I. Levey, Deqiang Qiu, Liping Zhao, William T. Hu, Duc M. Duong, Lenora Higginbotham, Eric B. Dammer, Nicholas T. Seyfried, Thomas S. Wingo, Chadwick M. Hales, Malu Gamez Tansey, David S. Goldstein, Anees Abrol, Vince D. Calhoun, Felicia C. Goldstein, Ihab Hajjar, Anne M. Fagan, Doug Galasko, Steven D. Edland, John Hanfelt, James J. Lah, David Weinshenker
Summary: The study demonstrated that atomoxetine, a clinically approved noradrenaline reuptake inhibitor, improved multiple Alzheimer's disease biomarkers in individuals with mild cognitive impairment. Treatment with atomoxetine significantly reduced CSF levels of Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism, and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits.
Article
Geriatrics & Gerontology
Alexis A. Bender, Rebecca L. McIntosh, Sean Sudduth, Michaela Harris, Kathy Tuckey, John C. Morgan, Joanna M. Jungerman, Abby Cox, Miranda A. Moore, Bryshia Ingram, Ellyn Pier, Theodore M. Johnson, David W. Loring, Kenneth Hepburn, Laura Medders, Allan Levey, James J. Lah, Chadwick M. Hales
Summary: GMN is an innovative care model aimed at improving access to accurate and timely diagnosis for patients with memory loss. It may help enhance the quality of life for patients and families through preventive and early care.
JOURNAL OF THE AMERICAN GERIATRICS SOCIETY
(2022)
Article
Neurosciences
Erik C. B. Johnson, E. Kathleen Carter, Eric B. Dammer, Duc M. Duong, Ekaterina S. Gerasimov, Yue Liu, Jiaqi Liu, Ranjita Betarbet, Lingyan Ping, Luming Yin, Geidy E. Serrano, Thomas G. Beach, Junmin Peng, Philip L. De Jager, Vahram Haroutunian, Bin Zhang, Chris Gaiteri, David A. Bennett, Marla Gearing, Thomas S. Wingo, Aliza P. Wingo, James J. Lah, Allan I. Levey, Nicholas T. Seyfried
Summary: This study analyzed the proteomes of over 1,000 brain tissues and identified new protein co-expression modules associated with Alzheimer's disease. These modules were highly conserved across cohorts and brain regions and revealed a proteopathic nature of the disease. The study also found disease-associated modules unique to the proteome, which could serve as potential therapeutic targets and biomarkers for Alzheimer's disease.
NATURE NEUROSCIENCE
(2022)
Article
Geriatrics & Gerontology
Aron S. Buchman, Lei Yu, Hans-Ulrich Klein, Andrea R. Zammit, Shahram Oveisgharan, Francine Grodstein, Shinya Tasaki, Allan Levey, Nicholas T. Seyfried, David A. Bennett
Summary: This study identified cortical proteins that may provide motor resilience in older adults. Five proteins were associated with progressive parkinsonism, suggesting their potential as therapeutic targets for maintaining motor function despite untreatable brain pathologies.
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Thomas S. Wingo, Ekaterina S. Gerasimov, Yue Liu, Duc M. Duong, Selina M. Vattathil, Adriana Lori, Jake Gockley, Michael S. Breen, Adam X. Maihofer, Caroline M. Nievergelt, Karestan C. Koenen, Daniel F. Levey, Joel Gelernter, Murray B. Stein, Kerry J. Ressler, David A. Bennett, Allan Levey, Nicholas T. Seyfried, Aliza P. Wingo
Summary: This study identified 11 genes that contribute to the pathogenesis of PTSD by regulating brain protein abundance. Seven of these genes were replicated in further studies and four also showed association with PTSD at the brain mRNA level. These findings provide promising targets for mechanistic and therapeutic studies for PTSD.
MOLECULAR PSYCHIATRY
(2022)
Article
Multidisciplinary Sciences
Sruti Rayaprolu, Sara Bitarafan, Juliet Santiago, Ranjita Betarbet, Sydney Sunna, Lihong Cheng, Hailian Xiao, Ruth S. Nelson, Prateek Kumar, Pritha Bagchi, Duc M. Duong, Annie M. Goettemoeller, Viktor Janos Olah, Matt Rowan, Allan Levey, Levi B. Wood, Nicholas T. Seyfried, Srikant Rangaraju
Summary: By using cell type-specific protein labeling, we can better study the proteomic differences between neurons and astrocytes, and identify potential factors related to neurological diseases.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Girija Goyal, Pranav Prabhala, Gautam Mahajan, Bruce Bausk, Tal Gilboa, Liangxia Xie, Yunhao Zhai, Roey Lazarovits, Adam Mansour, Min Sun Kim, Aditya Patil, Danielle Curran, Jaclyn M. Long, Sanjay Sharma, Abidemi Junaid, Limor Cohen, Thomas C. Ferrante, Oren Levy, Rachelle Prantil-Baun, David R. Walt, Donald E. Ingber
Summary: In this study, researchers successfully cultured human ectopic lymphoid follicles with similar characteristics to lymphoid follicles in a microfluidic chip. These follicles showed improved immune responses to vaccines and can serve as an alternative to non-human primates for preclinical evaluation.
Article
Clinical Neurology
Thomas S. Wingo, Ekaterina S. Gerasimov, Se Min Canon, James J. Lah, Allan Levey, Aliza P. Wingo
Summary: The study found that depression manifesting after age 50 is associated with a genetic predisposition to Alzheimer's disease (AD), suggesting that genetic predisposition may be a factor contributing to the pathogenesis of mid-life depression. Further study is needed to investigate whether there is a shared genetic basis between mid-life depression and AD.
ALZHEIMERS & DEMENTIA
(2023)
Article
Clinical Neurology
Richa Batra, Matthias Arnold, Maria A. Woerheide, Mariet Allen, Xue Wang, Colette Blach, Allan Levey, Nicholas T. Seyfried, Nilufer Ertekin-Taner, David A. Bennett, Gabi Kastenmuller, Rima F. Kaddurah-Daouk, Jan Krumsiek
Summary: This study provides a comprehensive investigation and description of AD-associated metabolic changes, laying the foundation for future mechanistic research.
ALZHEIMERS & DEMENTIA
(2023)
Article
Clinical Neurology
Aliza P. Wingo, Selina M. Vattathil, Jiaqi Liu, Wen Fan, David J. Cutler, Allan Levey, Julie A. Schneider, David A. Bennett, Thomas S. Wingo
Summary: This study found that LDL-C is associated with various neuropathological manifestations of AD independent of APOE, suggesting that LDL-C may be a modifiable risk factor for AD.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Article
Multidisciplinary Sciences
Caroline M. Watson, Eric B. Dammer, Lingyan Ping, Duc M. Duong, Erica Modeste, E. Kathleen Carter, Erik C. B. Johnson, Allan I. Levey, James J. Lah, Blaine R. Roberts, Nicholas T. Seyfried
Summary: Alzheimer's disease (AD) is the most common form of dementia, and CSF beta-amyloid, total Tau, and phosphorylated Tau (pTau) are sensitive and specific biomarkers for diagnosis. However, these biomarkers do not capture the complex changes in AD brain beyond amyloid and Tau pathologies. This study used SRM-MS with isotopically labeled standards to quantify CSF protein biomarkers, identifying proteins that could distinguish AD stages and cognitive impairment.
Article
Multidisciplinary Sciences
Zifan Jiang, Salman Seyedi, Rafi U. Haque, Alvince L. Pongos, Kayci L. Vickers, Cecelia M. Manzanares, James J. Lah, Allan I. Levey, Gari D. Clifford
Summary: This study utilized a computer vision-based deep learning model to analyze facial emotions expressed by individuals with cognitive impairment. The findings show that cognitive impairment is associated with differences in facial emotion expression, which can be used as an effective tool for screening cognitive impairment.
Article
Medicine, Research & Experimental
Xue Wang, Mariet Allen, Ozkan Is, Joseph S. Reddy, Frederick Q. Tutor-New, Monica Castanedes Casey, Minerva M. Carrasquillo, Stephanie R. Oatman, Yuhao Min, Yan W. Asmann, Cory Funk, Thuy Nguyen, Charlotte C. G. Ho, Kimberly G. Malphrus, Nicholas T. Seyfried, Allan I. Levey, Steven G. Younkin, Melissa E. Murray, Dennis W. Dickson, Nathan D. Price, Todd E. Golde, Nilufer Ertekin-Taner
Summary: This study found a significant correlation in the direction and magnitude of gene expression changes between Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), two neurodegenerative diseases. These changes were highly conserved between different brain regions and enriched in biological pathways. The findings have broad implications for the development of therapies and biomarkers for neurodegenerative diseases.
JOURNAL OF CLINICAL INVESTIGATION
(2022)