Article
Pharmacology & Pharmacy
Xavier Gomez-Santacana, Silvia Panarello, Xavier Rovira, Amadeu Llebaria
Summary: This review discusses the innovations in allosteric photopharmacology of metabotropic glutamate receptors (mGlu) and the new perspectives in understanding mGlu mechanisms, pharmacology, and (patho)physiology.
CURRENT OPINION IN PHARMACOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Ting-ting Fu, Gao Tu, Meng Ping, Guo-xun Zheng, Feng-yuan Yang, Jing-yi Yang, Yang Zhang, Xiao-jun Yao, Wei-wei Xue, Feng Zhu
Summary: This study utilized computational modeling approaches to reveal the subtype-selective mechanism of mGlu(1) and mGlu(5) receptors to different drug scaffolds, identifying critical residues that affect the binding of selective NAMs to the receptors. The results of this study can guide the rational design of novel NAMs.
ACTA PHARMACOLOGICA SINICA
(2021)
Review
Chemistry, Medicinal
Alshaima'a M. Qunies, Kyle A. Emmitte
Summary: Group II metabotropic glutamate (mGlu) receptors are promising targets for novel CNS therapeutics. This review summarizes patent applications for small molecule negative allosteric modulators (NAMs) targeting mGlu receptors between January 2015 and November 2020. Progress has been made in the discovery of new mGlu(2) NAMs, while mGlu(3) NAMs are more limited but show promise.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2021)
Article
Medicine, Research & Experimental
Abdullahi Ibrahim Uba, John Chea, Hannah Hoag, Mariya Hryb, Candice Bui-Linh, Chun Wu
Summary: This study investigates the binding mechanism between PAM CDPPB and mGluR5 using molecular dynamics simulations and molecular switch analysis. The results demonstrate that PAM CDPPB has a strong binding affinity, can induce conformational changes in the receptor, and stabilize the active conformation.
Article
Biochemistry & Molecular Biology
Xin Lin, Nicole M. Fisher, Shalini Dogra, Rebecca K. Senter, Carson W. Reed, Jacob J. Kalbfleisch, Craig W. Lindsley, Wesley B. Asher, Zixiu Xiang, Colleen M. Niswender, Jonathan A. Javitch
Summary: The activity of hippocampal SC-CA1 synapses is regulated by mGlu(7/8) heterodimers, and different mGlu(7) NAM compounds exhibit varying activity on these heterodimers.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Zhongtang Li, Guanxing Cai, Fan Fang, Wenchao Li, Minghua Fan, Jingjing Lian, Yinli Qiu, Xiangqing Xu, Xuehui Lv, Yiyan Li, Ruqiu Zheng, Yuxi Wang, Zhongjun Li, Guisen Zhang, Zhenming Liu, Zhuo Huang, Liangren Zhang
Summary: A series of furan-2-carboxamide analogues were identified as novel NMDAR-positive allosteric modulators, with FS2921 showing potential antidepressant effects. Compound 32h exhibited increased NMDAR excitability in vitro and significant antidepressant activity, with a favorable PK/PD profile. This study presents a new potential opportunity for discovering new antidepressants through novel NMDAR PAMs.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Neurosciences
Kimberly M. Holter, Alex D. Lekander, Christina M. LaValley, Elizabeth G. Bedingham, Bethany E. Pierce, L. Paul Sands, Craig W. Lindsley, Carrie K. Jones, Robert W. Gould
Summary: Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor subtype 5 (mGlu(5)) have shown anxiolytic and antidepressant effects, but concerns remain about potential adverse effects. Partial mGlu(5) NAMs, with submaximal levels of blockade, may have a broader therapeutic index than full mGlu(5) NAMs. Studies comparing M-5MPEP and VU0424238 found differences in their effects on sleep, cognition, and brain function, supporting the development of partial mGlu(5) NAMs.
FRONTIERS IN NEUROSCIENCE
(2021)
Article
Chemistry, Medicinal
Yousuke Yamada, Kristen Gilliland, Zixiu Xiang, Daniel Haymer, Katherine E. Crocker, Matthew T. Loch, Michael L. Schulte, Alice L. Rodriguez, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Bruce J. Melancon
Summary: The letter describes the synthesis and evaluation of two series of dual mGlu(2)/mGlu(3) positive allosteric modulators with moderate mGlu(3) potency and robust mGlu(2) potency. These compounds were shown to effectively modulate mGlu(3)-mediated signaling in central neurons.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
James J. J. Perkins, Paul McQuade, Christopher J. J. Bungard, Tracy L. L. Diamond, Liza T. T. Gantert, Anthony L. L. Gotter, Barbara Hanney, Ivory D. D. Hills, Danielle M. M. Hurzy, Aniket Joshi, Jonathan T. T. Kern, Kelly-Ann S. Schlegel, Jesse J. J. Manikowski, Zhaoyang Meng, Julie A. A. O'Brien, Anthony J. J. Roecker, Sean M. M. Smith, Jason M. M. Uslaner, Eric Hostetler, Robert S. S. Meissner
Summary: Modification of mGluR(2) NAM resulted in analogues with excellent binding affinity, lipophilicity, and suitable physicochemical properties for a PET tracer. [C-11]MK-8056 was synthesized and shown to have appropriate affinity, selectivity, and physicochemical properties for use as a positron emission tomography tracer for GluR(2).
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Neurosciences
Nather Madjid, Veronica Lidell, Gunnar Nordvall, Maria Lindskog, Sven-Ove Ogren, Pontus Forsell, Johan Sandin
Summary: This study aimed to examine the effects of positive allosteric modulators of neurotrophin/Trk receptor mediated signaling (Trk-PAM) on neurotransmitter release and depression-like behavior. The results showed that several compounds that potentiate Trk-receptor mediated signaling demonstrated antidepressant-like activity. Additionally, the data indicated that the effects of fluoxetine and ketamine in the forced swim test were mediated via BDNF/TrkB signaling, suggesting potential implications for novel therapies in MDD.
PSYCHOPHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Kirstie A. Bennett, Eugenia Sergeev, Cliona P. MacSweeney, Geor Bakker, Anne E. Cooper
Summary: This study demonstrates a unified brain exposure-receptor occupancy relationship for mGlu(5) negative allosteric modulators across different species and properties. Factors such as unbound brain concentration and receptor affinity play a crucial role in this relationship, showing less than a 10-fold overall difference and consistent with a simple E-max model.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2021)
Article
Chemistry, Medicinal
Maria J. Matos, Paula Novo, Lucia Mayan, Iria Torres, Eugenio Uriarte, Matilde Yanez, Jose Angel Fontenla, Francesco Ortuso, Stefano Alcaro, Francesca Procopio, Maria Isabel Rodriguez-Franco, Cristina Val, Maria I. Loza, Jose Brea, Fernanda Borges, Dolores Vina
Summary: Psychiatric and neurological disorders affect millions of people worldwide, and current treatments are limited in their effectiveness. New therapeutic solutions are urgently needed to improve the lives of patients.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Shahnawaz A. Bhat, Rebecca J. Henry, Alexa C. Blanchard, Bogdan A. Stoica, David J. Loane, Alan I. Faden
Summary: Research shows that mGluR5 PAM treatment post-TBI reduces pro-inflammatory microglial activation by modulating Akt/GSK-3 beta/CREB signaling, enhancing anti-inflammatory markers and promoting neuroprotection.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Monika Marcinkowska, Nikola Fajkis-Zajaczkowska, Katarzyna Szafranska, Jakub Jonczyk, Agata Siwek, Barbara Mordyl, Tadeusz Karcz, Gniewomir Latacz, Marcin Kolaczkowski
Summary: Modulating the alpha 1 beta 2 gamma 2 GABA-A receptor subpopulation in the basal ganglia region is a promising pharmacological strategy for neurological dysfunction. However, the current chemical space of molecules targeting the alpha 1/gamma 2 interface of GABA-A receptors is limited. In this study, we identified a series of 2-(4-fluorophenyl)-1H-benzo-[d]imidazoles as positive allosteric modulators (PAMs) with improved stability and reduced hepatotoxicity. These PAMs showed preference for interaction with the alpha 1/gamma 2 interface of the GABA-A receptor, providing useful chemical templates for further exploration of therapeutic potential.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Cell Biology
Jessica Brown, Ben Grayson, Joanna C. Neill, Michael Harte, Mark J. Wall, Richard T. Ngomba
Summary: The cognitive deficits of schizophrenia are caused by imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), leading to disrupted gamma oscillations. Two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, have been shown to restore cognitive deficits in a rodent model of schizophrenia by targeting PFC intracellular signalling molecules. In this study, gamma oscillatory activity was assessed in PFC slices from the rodent model, and the effects of the two PAMs were investigated. The results demonstrated that both VU0409551 and VU0360172 rescued the oscillatory deficits in a concentration-dependent manner, with the involvement of mGlu5 receptor modulation, PLC inhibition, and PKC inhibition.
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)