Article
Neurosciences
Ruth C. Werthmann, Manuel Tzouros, Jens Lamerz, Angelique Augustin, Thorsten Fritzius, Luca Trovo, Michal Stawarski, Adi Raveh, Catherine Diener, Christophe Fischer, Martin Gassmann, Lothar Lindemann, Bernhard Bettler
Summary: Recent studies have shown that mGlu1 and mGlu5 form functional heterodimers in the brain, exhibiting symmetric signal transduction where both protomers need to reach an active conformation for full receptor activity. This highlights differences in the signaling transduction of heterodimeric mGluRs that influence allosteric modulation.
Article
Pharmacology & Pharmacy
Vanessa Pereira, Juri Aparicio Arias, Amadeu Llebaria, Cyril Goudet
Summary: Neuropathic pain is a challenging condition to manage. In this study, the role of the amygdala in regulating neuropathic pain was investigated. The activation of mGlu4 receptors in the amygdala was found to alleviate sensory and depressive-like symptoms in a mouse model of neuropathy.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Multidisciplinary Sciences
Rens M. J. M. de Vries, Femke A. Meijer, Richard G. Doveston, Iris A. Leijten-van de Gevel, Luc Brunsveld
Summary: Cooperative ligand binding is an important phenomenon in biological systems, where the mechanism behind it remains poorly understood. Through studying ROR gamma t and solving 12 crystal structures bound to various orthosteric and allosteric ligands, it was found that the orthosteric ligand induces a clamping motion of the allosteric pocket via helices 4 to 5, with Ala355 shifting between helix 4 and 5.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Daniel H. Wolf, David Zheng, Christian Kohler, Bruce I. Turetsky, Kosha Ruparel, Theodore D. Satterthwaite, Mark A. Elliott, Mary E. March, Alan J. Cross, Mark A. Smith, Stephen R. Zukin, Ruben C. Gur, Raquel E. Gur
Summary: This study found individual differences in symptom reduction with the mGluR2 positive allosteric modulator AZD8529 in schizophrenia patients, as well as improved n-back fMRI activation. Despite no significant overall effects, drug versus placebo effects on brain region activation correlated with symptom reduction, suggesting broader effects across multiple symptom domains.
MOLECULAR PSYCHIATRY
(2022)
Article
Biology
Lei Liu, Zhiran Fan, Xavier Rovira, Li Xue, Salome Roux, Isabelle Brabet, Mingxia Xin, Jean-Philippe Pin, Philippe Rondard, Jianfeng Liu
Summary: G protein-coupled receptors (GPCRs) form homo- and heterodimers with allosteric cross-talk that fine-tunes transmembrane signaling. Investigating the action of positive allosteric modulators (PAMs) at the transmembrane interface of GABA(B) receptor revealed their specific modulation of GPCR dimers. The study showed that PAMs act at the active interface between transmembrane domains, impacting the function of GPCR dimers.
Article
Chemistry, Medicinal
Louise Dickson, Martin Teall, Elodie Chevalier, Toni Cheung, Gemma M. Liwicki, Stephen Mack, Anne Stephenson, Kathryn White, Richard Fosbeary, David C. Harrison, Nicola L. Brice, Kevin Doyle, Roberto Ciccocioppo, Chaobo Wu, Sarah Almond, Toshal R. Patel, Philip Mitchell, Matt Barnes, Andrew P. Ayscough, Lee A. Dawson, Mark Carlton, Roland W. Burli
Summary: In this study, highly potent and selective mGluR7 agonists, including CVN636, were identified, optimized, and characterized. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder, suggesting its potential as a drug candidate in CNS disorders involving mGluR7 and glutamatergic dysfunction.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Louise Dickson, Martin Teall, Elodie Chevalier, Toni Cheung, Gemma M. Liwicki, Stephen Mack, Anne Stephenson, Kathryn White, Richard Fosbeary, David C. Harrison, Nicola L. Brice, Kevin Doyle, Roberto Ciccocioppo, Chaobo Wu, Sarah Almond, Toshal R. Patel, Philip Mitchell, Matt Barnes, Andrew P. Ayscough, Lee A. Dawson, Mark Carlton, Roland W. Burli
Summary: In this study, highly potent and selective agonists for the low affinity metabotropic glutamate receptor mGluR7 were identified, optimized, and characterized. The chromane CVN636, in particular, showed exceptional selectivity for mGluR7 and demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. As such, CVN636 has the potential to be a drug candidate for CNS disorders involving mGluR7 and glutamatergic dysfunction.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Neurosciences
G. Martella, P. Bonsi, P. Imbriani, G. Sciamanna, H. Nguyen, L. Yu-Taeger, M. Schneider, S. M. Poli, R. Lutjens, A. Pisani
Summary: Impairment of long-term synaptic plasticity is a unique endophenotype of certain forms of dystonia. Broad-spectrum antimuscarinic drugs and negative allosteric modulators of metabotropic glutamate receptor subtypes may be potential therapeutic options for dystonia treatment. The findings suggest common signaling pathway dysfunction among distinct dystonia genes and indicate the potential of dipraglurant as a novel therapeutic agent for this debilitating disorder.
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)
Article
Neurosciences
Prachi Ojha, Subhajit Pal, Samarjit Bhattacharyya
Summary: Norbin protein plays a critical role in the internalization process of Group I mGluRs and may be associated with mGluR-mediated synaptic plasticity.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Shivani Choudhary, Melanie Abongwa, Sudhanva S. Kashyap, Saurabh Verma, Gunnar R. Mair, Daniel Kulke, Richard J. Martin, Alan P. Robertson
Summary: In this study, a GluCls subunit from Brugia malayi was cloned and its pharmacological properties were investigated. The results showed that the receptor was regulated by the natural ligand L-glutamate and ivermectin, and had dual effects when exposed to nodulisporic acid. Furthermore, the unique pharmacological characteristics of this GluCls subunit could explain the variation in drug sensitivities observed in different nematode parasites.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Neurosciences
Chloe Geoffroy, Pierre Paoletti, Laetitia Mony
Summary: NMDA receptors play essential roles in synaptic transmission and plasticity, with both hyper- and hypo-activation being detrimental to neuronal function. Recent developments in NMDAR positive allosteric modulators (PAMs) have provided new insights into potential treatments for conditions like schizophrenia and Alzheimer's disease. Further research is needed to fully understand the physiological effects and therapeutic potential of these modulators in vivo.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Article
Cell Biology
Mengrong Li, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, Jingjing Guo
Summary: The identification and development of non-peptide allosteric modulators for PTH1R have gained attention. It has been found that a negative allosteric modulator (NAM) inhibits the activation of PTH1R, but the mechanism is unclear. Molecular dynamics simulations and analytical approaches reveal that NAM destabilizes the PTH1R-PTH-spep/qpep complexes, weakens PTH/peps-PTH1R binding, and reduces intra- and inter-molecular couplings in PTH1R. Compared with positive allosteric effects induced by extracellular Ca2+, the negative allosteric regulator significantly reduces the correlation between PTH and G-protein binding sites. These findings contribute to the development of new therapeutics for diseases caused by PTH1R abnormal activation.
Review
Endocrinology & Metabolism
Siyuan Shen, Chang Zhao, Chao Wu, Suyue Sun, Ziyan Li, Wei Yan, Zhenhua Shao
Summary: GPCRs, as the largest family of transmembrane proteins, regulate various physiological processes. However, their complicated signal transduction pathways and difficulties in drug development have presented challenges. By identifying new ligands that bind to allosteric sites, safer drugs for treating various diseases can be designed.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Cell Biology
Simon Lind, Dagny Olofsson Hoffmann, Huamei Forsman, Claes Dahlgren
Summary: By studying the effects of the FFA2R ligand GLPG0974 on neutrophil activation, we discovered that GLPG0974 acts as an antagonist, agonist, and positive modulator of FFA2R. It affects NADPH-oxidase activity and alters receptor-downstream signaling induced by the co-agonistic PAMs.
CELLULAR SIGNALLING
(2022)
Review
Biochemistry & Molecular Biology
Ramasamy Thilagavathi, Maryam Sadat Hosseini-Zare, Manokaran Malini, Chelliah Selvam
Summary: Glucokinase is an important enzyme in the liver and pancreatic cells of humans, promoting glycogen synthesis and insulin release. Research on glucokinase as a drug target for type 2 diabetes has generated interest, but clinical development has faced challenges.
CHEMICAL BIOLOGY & DRUG DESIGN
(2022)
Article
Biochemistry & Molecular Biology
Matej Gazdarica, Judith Noda, Oleh Durydivka, Vendula Novosadova, Ken Mackie, Jean-Philippe Pin, Laurent Prezeau, Jaroslav Blahos
Summary: CB1R signaling is regulated by receptor desensitization and the protein SGIP1, which plays an important role in controlling CB1R function and its involvement in pathological conditions.
JOURNAL OF NEUROCHEMISTRY
(2022)
Article
Neurosciences
Francine C. Acher, Alexandre Cabaye, Floriane Eshak, Anne Goupil-Lamy, Jean-Philippe Pin
Summary: Metabotropic glutamate receptors (mGluRs) have attracted attention as therapeutic targets for psychiatric and neurological disorders. This review focuses on the pharmacology and structural organization of mGluRs, particularly on the orthosteric ligands and allosteric modulators interacting with the glutamate binding domain.
Article
Chemistry, Multidisciplinary
Kandhan Palanisamy, S. M. Esther Rubavathy, Muthuramalingam Prakash, Ramasamy Thilagavathi, Maryam S. Hosseini-Zare, Chelliah Selvam
Summary: This study screened natural products and ionic liquids against the main protease (Mpro) of SARS-CoV-2 and identified compounds NP-Hit2 and NP-Hit3 with strong binding affinity to Mpro. Cholinium-based ionic liquids naproxenate, ketoprofenate, and geranate also showed strong interactions with Mpro and exhibited antimicrobial properties.
Letter
Cell Biology
Wei Fang, Fan Yang, Chanjuan Xu, Shenglong Ling, Li Lin, Yingxin Zhou, Wenjing Sun, Xiaomei Wang, Peng Liu, Philippe Rondard, Pan Shi, Jean-Philippe Pin, Changlin Tian, Jianfeng Liu
Article
Neurosciences
Cecile Derieux, Audrey Leaute, Agathe Brugoux, Deborah Jaccaz, Claire Terrier, Jean-Philippe Pin, Julie Kniazeff, Julie Le Merrer, Jerome A. J. Becker
Summary: Chronic sodium bromide treatment was found to alleviate autistic-like behaviors in three genetic mouse models of autism, with superior effects in Oprm1(-/-) mice compared to chronic bumetanide administration. Additionally, a positive allosteric modulator (PAM) of mGlu4 receptor showed synergistic effects with chronic NaBr treatment on autistic-like behavior in Oprm1(-/-) mice.
NEUROPSYCHOPHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Ramasamy Thilagavathi, Sridhar Priyankha, Manivel Kannan, Muthuramalingam Prakash, Chelliah Selvam
Summary: Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease caused by genetic mutations or overexpression. Chemotherapy and immunotherapy are common treatments, but the response rates are still low. Natural compounds derived from plants show promising inhibitory effects on TNBC, with advantages such as low toxicity and easy accessibility, making them important for the development of effective anti-tumor therapies.
CHEMICAL BIOLOGY & DRUG DESIGN
(2023)
Article
Chemistry, Physical
Kandhan Palanisamy, K. Rudharachari Maiyelvaganan, Shanmugasundaram Kamalakannan, Ramasamy Thilagavathi, Chelliah Selvam, Muthuramalingam Prakash
Summary: This study identified several compounds as potential drug targets for inhibiting SARS-CoV-2-related diseases, and these compounds exhibited potential drug-like properties and stability. Among them, asarinin was found to be the most effective inhibitor and may serve as a potent antiviral agent.
MOLECULAR SIMULATION
(2023)
Review
Biochemistry & Molecular Biology
Mireille Elodie Tsitokana, Pierre-Andre Lafon, Laurent Prezeau, Jean-Philippe Pin, Philippe Rondard
Summary: Therapeutic antibodies for the treatment of central nervous system diseases have been extensively studied, resulting in approved monoclonal antibodies for brain disease therapies. Additionally, non-invasive antibody-based imaging approaches have been explored for biomarker detection in brain cancers. However, the low ability of antibodies to cross the blood-brain barrier has led to the investigation of single-domain antibodies (sdAbs) as an alternative. While the brain uptake of these small antibodies is initially low, there is a growing number of studies reporting brain-penetrating sdAbs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
S. M. Esther Rubavathy, Kandhan Palanisamy, S. Priyankha, Ramasamy Thilagavathi, Muthuramalingam Prakash, Chelliah Selvam
Summary: In this study, HDAC8 inhibitors with high affinity and good ADMET characteristics were screened from a natural product database. Through molecular docking, molecular dynamics, and MM-PBSA analysis, it was found that these compounds have strong binding affinity and are more effective than romidepsin. These findings may contribute to further development of HDAC8 inhibitors.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Pharmacology & Pharmacy
Vanessa Pereira, Juri Aparicio Arias, Amadeu Llebaria, Cyril Goudet
Summary: Neuropathic pain is a challenging condition to manage. In this study, the role of the amygdala in regulating neuropathic pain was investigated. The activation of mGlu4 receptors in the amygdala was found to alleviate sensory and depressive-like symptoms in a mouse model of neuropathy.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Environmental Sciences
Manivel Kannan, Ramasamy Thilagavathi, Chelliah Selvam
Summary: This study synthesized a curcumin benzothiazole analogue and evaluated its antioxidant properties, in vitro anticancer activity, and in vivo toxicity. The results showed that the analogue exhibited strong antioxidant activity and the highest cytotoxic activity against MDA MB 231 breast cancer cells. The substance was found to be safe up to levels of 300 mg/kg in albino wistar rats.
TOXICOLOGY AND ENVIRONMENTAL HEALTH SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Sridhar Priyankha, Varatharaj Rajapandian, Kandhan Palanisamy, S. M. Esther Rubavathy, Ramasamy Thilagavathi, Chelliah Selvam, Muthuramalingam Prakash
Summary: Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease caused by missing certain receptors. In this study, researchers screened natural products and identified six hit compounds with strong binding affinity towards the protein PARP-1, which is involved in the development of TNBC. Molecular dynamics simulations and calculations showed that two of these compounds had stronger binding energies with PARP-1 than an FDA-approved PARPi. The study offers valuable insights for the potential use of PARPi in TNBC treatment, and the findings were validated through comparison with an FDA-approved PARPi.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Review
Pharmacology & Pharmacy
Kumararaja Gayathri, Mahendran Bhaskaran, Chelliah Selvam, Ramasamy Thilagavathi
Summary: Curcumin, derived from the rhizomes of Curcuma longa Linn, has been extensively studied for its potential in treating various diseases. However, its inadequate intake and low aqueous solubility have posed challenges. To overcome these challenges, nanotechnology has been used to improve the absorption, solubility, and bioavailability of curcumin. Nano formulations of curcumin have shown promise in overcoming the limitations of traditional curcumin-based medications.
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
(2023)
Review
Chemistry, Medicinal
Ramasamy Thilagavathi, S. Sameema Begum, Sowfika Dharshini Varatharaj, Arun Kumar Balasubramaniam, Joselin Susan George, Chelliah Selvam
Summary: Liver problems are a global concern and conventional therapies are ineffective. Protecting the liver is crucial for good health. Infections, immune issues, cancer, alcohol abuse, and drug overdose can cause liver diseases. Antioxidants from plants and dietary sources can protect the liver from oxidative stress and chemicals. Plant-derived compounds such as flavonoids, alkaloids, terpenoids, polyphenolics, sterols, anthocyanins, and saponin glycosides show hepatoprotective potential. More research is needed to develop safer and more potent phytochemical drugs for treating liver diseases.
PHYTOTHERAPY RESEARCH
(2023)
Correction
Neurosciences
Lucia Privitera, Ellen L. Hogg, Matthias Gaestel, Mark J. Wall, Sonia A. L. Correa
Article
Neurosciences
Li-Ya Jiang, Guan-Hao Wang, Jing-Jiao Xu, Xiao-Li Li, Xiao-Yan Lin, Xiang Fang, Hong-Xu Zhang, Mei Feng, Chun-Ming Jiang
Summary: This study reveals the importance of LINC00473 in regulating temozolomide (TMZ) resistance in glioblastoma (GB) and its potential mechanism. By regulating the expression of CEBP alpha and MGMT, LINC00473 promotes the formation of chemoresistance. Furthermore, LINC00473 can transfer chemoresistance to adjacent sensitive cells through exosomes.
Article
Neurosciences
Olga Kopach, Tetyana Pivneva, Nataliya Fedirko, Nana Voitenko
Summary: This study found that diabetic animals exhibit severe xerostomia characterized by reduced saliva flow rate, diminished total protein content, and decreased amylase activity. The impaired saliva production in diabetes is associated with reduced and delayed intracellular Ca2+ signals in submandibular acinar cells, caused by malfunctioning mitochondria. Targeting malfunctioning mitochondria may be a potential strategy for the treatment of diabetic xerostomia.
Article
Neurosciences
Nicholas M. Timme, Cherish E. Ardinger, Seth D. C. Weir, Rachel Zelaya-Escobar, Rachel Kruger, Christopher C. Lapish
Summary: This study aimed to assess aversion-resistant drinking behavior in head-fixed mice and explore the relationship between non-consummatory behaviors and aversion-resistant drinking. The results showed that head-fixed mice exhibited heterogenous levels of aversion-resistant drinking and non-consummatory behaviors were related to the intensity of this behavior.
Article
Neurosciences
David R. Maguire, Charles P. France
Summary: Methocinnamox (MCAM) is a novel, long-acting opioid receptor antagonist that effectively decreases fentanyl self-administration and prevents opioid overdose in monkeys. The study demonstrates the potential therapeutic utility of MCAM in the treatment of opioid use disorder.
Article
Neurosciences
Xiang Li, Dan Feng, Shenglu Ma, Mingxing Li, Shulei Zhao, Man Tang
Summary: This study investigated the effects of fluoxetine on neurochemical, neurobiological, and neurobehavioral changes in different subregions of the hippocampus. The results showed that fluoxetine increased dialysate 5-HT, decreased membrane 5-HTT protein, and increased cytoplasmic fraction. Additionally, fluoxetine reduced immobility times in behavioral tests, with greater effects observed in the ventral subregion compared to the dorsal subregion.
Article
Neurosciences
Alexander V. Zholos, Mariia I. Melnyk, Dariia O. Dryn
Summary: Acetylcholine is an important neurotransmitter in visceral smooth muscles, activating M2 and M3 muscarinic receptors to cause smooth muscle excitation and contraction. This review focuses on the cellular and molecular mechanisms underlying acetylcholine-induced depolarisation and smooth muscle contraction, as well as the effects of anticholinergic drugs on gastrointestinal motility. The knowledge gained from recent studies has greatly expanded our understanding of these processes.
Article
Neurosciences
Zhenlong Li, Hsien-Yu Peng, Chau-Shoun Lee, Tzer-Bin Lin, Ming-Chun Hsieh, Cheng-Yuan Lai, Han-Fang Wu, Lih-Chyang Chen, Mei-Ci Chen, Dylan Chou
Summary: Methylone shows significant efficacy in treating depression and social deficits, making it an ideal candidate for anti-depressant medication.
Article
Neurosciences
Aline Freyssin, Allison Carles, Sarra Guehairia, Gilles Rubinstenn, Tangui Maurice
Summary: This study explores the potential of combining FENM and S1R agonists in the treatment of Alzheimer's disease. The results showed that most FENM-based combinations can protect against learning deficits caused by A beta 25-35, with better efficacy in short-term memory.
Article
Neurosciences
J. D. Lorente, J. Cuitavi, L. Rullo, S. Candeletti, P. Romualdi, L. Hipolito
Summary: This study analyzed the effects of pain on negative affect in different sexes and time courses, as well as the involvement of the dynorphinergic and corticotropin releasing factor systems in these pain-related behaviors. The results showed sex and time-dependent anxiety- and anhedonia-like behaviors induced by pain in female rats. The recruitment of KOR/DYN in the NAc was identified as a key neurological substrate mediating pain-induced behavioral alterations.
Article
Neurosciences
Rongjun Liu, Daofan Sun, Xiuzhong Xing, Qingge Chen, Bo Lu, Bo Meng, Hui Yuan, Lan Mo, Liufang Sheng, Jinwei Zheng, Qiusheng Wang, Junping Chen, Xiaowei Chen
Summary: The coexistence of pain and depression is frequently observed in patients with chronic pain and depression. Oxytocin, a neuropeptide, has been reported to relieve chronic pain and depressive symptoms. This study investigated the effect of intranasal oxytocin on neuropathic pain and comorbid depressive symptoms, and found that oxytocin attenuated depression-like behavior but did not alleviate mechanical hyperalgesia. The results suggest that intranasal oxytocin may have the potential to treat depressive symptoms in neuropathic pain patients.
