Article
Chemistry, Medicinal
Rory A. Capstick, David Whomble, Douglas L. Orsi, Andrew S. Felts, Alice L. Rodriguez, Paige N. Vinson, Sichen Chang, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Carrie K. Jones, Craig W. Lindsley, Changho Han
Summary: The lack of suitable tool compounds has restricted the in vivo understanding of M5 receptor biology. In this article, the authors present their ongoing efforts to develop next-generation M5 antagonists with improved clearance profiles.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Douglas L. Orsi, Andrew S. Felts, Alice L. Rodriguez, Paige N. Vinson, Hyekyung P. Cho, Sichen Chang, Anna L. Blobaum, Colleen M. Niswender, Jeffrey Conn, Carrie K. Jones, Craig W. Lindsley, Changho Han
Summary: This Letter describes the ongoing effort to improve the clearance of selective M5 antagonists, reporting the replacement of the previously disclosed piperidine amide with a pyrrolidine amide core. The compounds in this series showed good potency, subtype selectivity, and moderate to low clearance profiles. Interestingly, the SAR for this series diverged from previous efforts.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Pharmacology & Pharmacy
Ye Jiang, Mahmuda Yeasmin, Arisbel B. Gondin, Arthur Christopoulos, Celine Valant, Wessel A. C. Burger, David M. Thal
Summary: This study investigated the activation of individual G protein subfamilies and downstream signaling pathways of compounds 6A and 7A at the M-2 mAChR. The results showed that M-2 mAChR primarily couples to Galpha(i/o) and Galpha(s), but no Galpha(i) bias was detected for compounds 6A and 7A. This highlights the importance of cellular background in classifying new ligands.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
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
Biochemistry & Molecular Biology
Yaopeng Zhao, Jixia Wang, Tao Hou, Yancheng Yu, Han Zhou, Yang Han, Junxiang Cheng, Yanfang Liu, Chaoran Wang, Long Chen, Xinmiao Liang
Summary: A series of 2-(2,2-diarylethyl)-cyclamine derivatives were designed and synthesized as M3 mAChR antagonists, showing excellent selectivity and antagonistic activity. These novel compounds have the potential to be candidates for COPD drug development.
BIOORGANIC CHEMISTRY
(2023)
Article
Food Science & Technology
Petrus Siregar, Gilbert Audira, Ling-Yi Feng, Jia-Hau Lee, Fiorency Santoso, Wen-Hao Yu, Yu-Heng Lai, Jih-Heng Li, Ying-Ting Lin, Jung-Ren Chen, Chung-Der Hsiao
Summary: Arecoline, a nicotinic acid-based alkaloid found in betel nut, induces locomotor hyperactivity in zebrafish larvae even at low concentrations. Molecular docking and antagonist co-exposure experiments revealed the involvement of multiple muscarinic acetylcholine receptors in mediating the effects of arecoline on zebrafish behavior. Co-incubation with M1 to M4 mAChR antagonists rescued the locomotion hyperactivity phenotypes triggered by arecoline, indicating its potent hyperactivity-stimulating effects.
Article
Biochemistry & Molecular Biology
Miriana Scordino, Monica Frinchi, Giulia Urone, Domenico Nuzzo, Giuseppa Mudo, Valentina Di Liberto
Summary: The differentiation of neural progenitors involves complex regulatory mechanisms that can be modulated by signals such as HSP70 and SOD1. These regulatory mechanisms are crucial for understanding stem cell and cancer research and therapy. In this study, the expression of HSP70 and SOD1 was found to play a role in promoting cell survival and protecting against oxidative stress-induced damage during the differentiation process of SH-SY5Y cells.
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.
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
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
Developmental Biology
Rishav Mitra, Shlesha Richhariya, Siddharth Jayakumar, Dimple Notani, Gaiti Hasan
Summary: In fruit fly larvae, the IP3/Ca2+ signals in specific interneurons drive the expression of Set2 gene, essential for pupariation in the absence of dietary protein. This signal-controlled expression of Set2 upregulates key Ca2+-signaling genes through a positive-feedback loop, regulating gene expression for the transition from larval to pupal stages.
Article
Multidisciplinary Sciences
Tomor Harnod, Yu-Cih Yang, Lu-Ting Chiu, Jen-Hung Wang, Shinn-Zong Lin, Dah-Ching Ding
Summary: This study used data from the Taiwan National Health Insurance Research Database to investigate the association between bladder antimuscarinic use and dementia risk in patients aged 55 years or older. The study found that Taiwanese patients who used bladder antimuscarinics for more than 1 year had a significantly higher risk of developing dementia compared to those who did not use this treatment. Additionally, the risk of dementia increased proportionally with higher doses of antimuscarinics and longer duration of use.
SCIENTIFIC REPORTS
(2021)
Article
Pharmacology & Pharmacy
Sandesh P. Kamdi, Hemant R. Badwaik, Amit Raval, Ajazuddin, Kartik T. Nakhate
Summary: Phloridzin reverses diabetes-induced memory impairment by upregulating neurotrophic factors, reducing oxidative stress, and increasing cholinergic signaling in the brain.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
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
Behavioral Sciences
Naoya Aoki, Chihiro Mori, Toshiyuki Fujita, Shouta Serizawa, Shinji Yamaguchi, Toshiya Matsushima, Koichi J. Homma
Summary: This study investigates the specific subtypes of muscarinic acetylcholine receptors (mAChRs) that play a critical role in imprinting. The results suggest that excitatory receptor subtypes M-3 and M-5 and inhibitory receptor subtype M-2 and/or M-4 work together to achieve a balanced acetylcholine signaling for successful imprinting.
BEHAVIOURAL BRAIN RESEARCH
(2022)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)