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
Neurosciences
Sakiko Taniguchi, Jacob R. Stolz, Geoffrey T. Swanson
Summary: Perampanel (PMP) has been found to inhibit both AMPAR and KARs, suggesting that its clinical actions may arise from selective inhibition of different glutamate receptor signaling pathways.
JOURNAL OF NEUROSCIENCE
(2022)
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)
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
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
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
Kiran Sapkota, Erica S. Burnell, Mark W. Irvine, Guangyu Fang, Dinesh Y. Gawande, Shashank M. Dravid, David E. Jane, Daniel T. Monaghan
Summary: The study characterizes a novel NMDAR antagonist, UBP792, which displays partial subtype-selectivity and inhibits NMDAR responses by reducing the potency and efficacy of L-glutamate and glycine. It acts non-competitively, with activity independent of voltage and affected by pH, and potentially stabilizes different channel conformations to inhibit NMDAR function. This expands the possibilities for developing NMDAR modulators with appropriate selectivity for therapeutic indications.
Article
Neurosciences
Agata Ploska, Paulina Cieslik, Anna Siekierzycka, Leszek Kalinowski, Joanna M. Wieronska
Summary: The olfactory bulbectomized rat model can be used to study depression and Alzheimer's disease, with neurochemical changes in OBX animals resembling those associated with AD pathology. CDPPB can improve cognitive impairment in the passive avoidance test and partially reverse the changes in nitric oxide synthase expression induced by the lesion.
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.
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
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
Biochemistry & Molecular Biology
Nina Treder, Albert Martinez-Pinteno, Natalia Rodriguez, Nestor Arbelo, Santiago Madero, Marta Gomez, Clemente Garcia-Rizo, Sergi Mas, Patricia Gasso, Eduard Parellada, Constanza Moren
Summary: Schizophrenia is a heterogeneous mental disorder that affects approximately 1% of the global population. One of the main pathophysiological theories suggests an imbalance between excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, involving N-methyl-D-aspartate receptors (NMDAr). This imbalance may lead to excessive glutamate storms, dendritic pruning, and cellular stress, including nitrosative stress mediated by nitric oxide (NO). The administration of NMDAr antagonists has been found to increase nitric oxide synthase (NOS) levels in specific brain regions, suggesting a potential target for early treatments. In a murine model, the protein levels of NOS were analyzed in the prefrontal cortex (PFC) and ventral hippocampus (HPC) after ketamine-induced schizophrenia, as well as after treatment with clozapine (CLZ) or JNJ-46356479 (JNJ). The findings suggest a dysregulation of the NOS system following NMDAr antagonist administration, which can be modulated by early CLZ and JNJ treatments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Chemistry, Medicinal
Zoltan Orgovan, Gyorgy G. Ferenczy, Gyorgy M. Keseru
Summary: Metabotropic glutamate receptors are C class G protein-coupled receptors with relevance in various psychiatric and neurological disorders, making them of considerable interest for drug development. Allosteric modulators offer advantages over orthosteric ligands, but challenges such as structure-activity relationships and pharmacological changes make optimizing them into drug candidates challenging. Subtle structural changes identified as molecular switches may modulate the functional activity of allosteric ligands in this receptor family.
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.
Article
Clinical Neurology
Kristopher M. Kahlig, Liam Scott, Robert J. Hatch, Andrew Griffin, Gabriel Martinez Botella, Zoe A. Hughes, Marion Wittmann
Summary: This study investigated the effects of PRAX-562 on sodium current, neuronal excitability, and protection from evoked seizures. PRAX-562 demonstrated potent inhibition of persistent sodium current and significantly improved tolerability compared to standard sodium channel blockers. It showed robust preclinical anticonvulsant activity and potentially represents a differentiated therapeutic option for hyperexcitability disorders.
Review
Geriatrics & Gerontology
Zackary A. Cope, Takeshi Murai, Stacey J. Sukoff Rizzo
Summary: Emerging data suggest that sub-clinical, non-convulsive epileptiform activity is prevalent in Alzheimer's disease (AD) and can be detected early in the disease. It is also correlated with cognitive decline in both humans and animal models. Epileptiform activity and electroencephalographic (EEG) measures have untapped potential to enhance the translational validity of AD-related biomarkers in animal models.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Correction
Geriatrics & Gerontology
Kevin P. Kotredes, Adrian Oblak, Ravi S. Pandey, Peter Bor-Chian Lin, Dylan Garceau, Harriet Williams, Asli Uyar, Rita O'Rourke, Sarah O'Rourke, Cynthia Ingraham, Daria Bednarczyk, Melisa Belanger, Zackary Cope, Kate E. Foley, Benjamin A. Logsdon, Lara M. Mangravite, Stacey J. Sukoff Rizzo, Paul R. Territo, Gregory W. Carter, Michael Sasner, Bruce T. Lamb, Gareth R. Howell
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Review
Hematology
Selen C. Muratoglu, Marc F. Charette, Zorina S. Galis, Adam S. Greenstein, Alan Daugherty, Anne Joutel, Beth A. Kozel, Donna M. Wilcock, Emily C. Collins, Farzaneh A. Sorond, Gareth R. Howell, Hyacinth I. Hyacinth, Kent K. C. Lloyd, Kurt R. Stenmark, Manfred Boehm, Mark L. Kahn, Roderick Corriveau, Sara Wells, Timothy J. Bussey, Stacey J. Sukoff Rizzo, M. Luisa Iruela-Arispe
Summary: Clinical investigations have shown that vascular-associated medical conditions are significant risk factors for dementia. However, the specific cognitive impairments associated with certain types of vascular deficiencies are still unclear. To address this, the National Heart, Lung, and Blood Institute has developed animal models to study vascular disease and its underlying causes. These models could be used as tools to link specific vascular signaling pathways with cognitive and neurobehavioral deficits related to dementia.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2022)
Article
Clinical Neurology
Liam Scott, Corey B. Puryear, Gabriel M. Belfort, Shane Raines, Zoe A. Hughes, Lillian G. Matthews, Bernard Ravina, Marion Wittmann
Summary: This study assessed the pharmacologic activity and tolerability of the T-type calcium channel blocker PRAX-944 in a rat tremor model and healthy participants. The results showed that PRAX-944 reduced tremor and sigma power in rats, and similar reductions in sigma power were observed in healthy participants. These findings suggest that PRAX-944 holds promise for reducing tremor in patients with essential tremor.
MOVEMENT DISORDERS
(2022)
Article
Medicine, General & Internal
Olivier Perche, Fabien Lesne, Alain Patat, Susanne Raab, Roy Twyman, Robert H. Ring, Sylvain Briault
Summary: This study describes a case of a 25-year-old Caucasian male with autism spectrum disorder and severe intellectual disability, presenting large-conductance calcium-activated potassium channel haploinsufficiency due to a de novo balanced translocation. The findings suggest a direct link between KCNMA1 gene disruption and visual dysfunction in humans, likely due to bipolar cell dysfunction.
JOURNAL OF MEDICAL CASE REPORTS
(2022)
Article
Geriatrics & Gerontology
Adrian L. Oblak, Kevin P. Kotredes, Ravi S. Pandey, Alaina M. Reagan, Cynthia Ingraham, Bridget Perkins, Christopher Lloyd, Deborah Baker, Peter B. Lin, Disha M. Soni, Andy P. Tsai, Scott A. Persohn, Amanda A. Bedwell, Kierra Eldridge, Rachael Speedy, Jill A. Meyer, Johnathan S. Peters, Lucas L. Figueiredo, Michael Sasner, Paul R. Territo, Stacey J. Sukoff Rizzo, Gregory W. Carter, Bruce T. Lamb, Gareth R. Howell
Summary: Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). This study evaluated the impact of genetic risk factors on late-onset AD in mice fed with a high fat/high sugar diet and found a correlation between obesity and late-onset AD.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Behavioral Sciences
Sarah A. A. Schoenrock, Leona Gagnon, Ashley Olson, Michael Leonardo, Vivek M. M. Philip, Hao He, Laura G. G. Reinholdt, Stacey J. Sukoff J. Rizzo, James D. D. Jentsch, Elissa J. J. Chesler, Lisa M. M. Tarantino
Summary: The use of cocaine and overdose deaths related to cocaine have increased in the United States in the past decade. Despite the lack of approved treatments for cocaine use disorder (CUD), genetic studies in mice have provided valuable insights into its etiology. This study used a 19-day protocol to measure cocaine-induced behavioral sensitization in genetically diverse mouse strains, identifying significant differences in cocaine sensitivity and sensitization. These behaviors exhibited robust heritability, suggesting they can be utilized in future genetic mapping studies and the development of novel therapeutics.
FRONTIERS IN BEHAVIORAL NEUROSCIENCE
(2022)
Article
Clinical Neurology
Michael Sasner, Paul R. Territo, Stacey J. Sukoff J. Rizzo
Summary: The second annual workshop on improving preclinical to clinical translation in Alzheimer's Disease Research provided participants with skills and knowledge to perform preclinical experiments and improve translational studies for AD. The workshop included lectures, hands-on training, and participants from various research stages and regions.
ALZHEIMERS & DEMENTIA
(2023)
Editorial Material
Behavioral Sciences
Stacey J. Sukoff Rizzo
NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
(2023)
Correction
Biology
Thomas Ridler, Jonathan Witton, Keith G. Phillips, Andrew Randall, Jonathan T. Brown
Article
Geriatrics & Gerontology
Stacey J. Sukoff Rizzo, Toren Finkel, Susan L. Greenspan, Neil M. Resnick, Jennifer S. Brach
Summary: Research on aging is at a crucial stage where findings in basic biology can be applied to improve health span and longevity. The collaboration of researchers from various disciplines is essential in identifying new biomarkers, therapeutic targets, and assessing the efficacy of interventions. The ultimate goal is to conduct clinical trials of novel agents to extend health span and lifespan.
INNOVATION IN AGING
(2023)
Article
Clinical Neurology
Kristen D. Onos, Sara K. Quinney, David R. Jones, Andrea R. Masters, Ravi Pandey, Kelly J. Keezer, Carla Biesdorf, Ingrid F. Metzger, Jill A. Meyers, Johnathon Peters, Scott C. Persohn, Brian P. McCarthy, Amanda A. Bedwell, Lucas L. Figueiredo, Zackary A. Cope, Michael Sasner, Gareth R. Howell, Harriet M. Williams, Adrian L. Oblak, Bruce T. Lamb, Gregory W. Carter, Stacey J. Sukoff Rizzo, Paul R. Territo
Summary: This study investigates the pharmacokinetic/pharmacodynamic (PK/PD) relationship of levetiracetam (LEV) in an amyloidogenic mouse model of Alzheimer's disease (AD). The results demonstrate non-linear kinetics based on dose and sex, with significant sex differences in the pharmacokinetics of LEV observed in 5XFAD mice. Additionally, gene expression changes relevant to human AD were found to be dose-related and aligned with regional changes in glucose uptake. The study highlights the importance of PK/PD relationships in preclinical studies to inform clinical study design.
ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS
(2022)
Article
Clinical Neurology
Adrian L. Oblak, Zackary A. Cope, Sara K. Quinney, Ravi S. Pandey, Carla Biesdorf, Andi R. Masters, Kristen D. Onos, Leslie Haynes, Kelly J. Keezer, Jill A. Meyer, Jonathan S. Peters, Scott A. Persohn, Amanda A. Bedwell, Kierra Eldridge, Rachael Speedy, Gabriela Little, Sean-Paul Williams, Brenda Noarbe, Andre Obenaus, Michael Sasner, Gareth R. Howell, Gregory W. Carter, Harriet Williams, Bruce T. Lamb, Paul R. Territo, Stacey J. Sukoff Rizzo
Summary: This study aimed to evaluate the effectiveness of BACE inhibitor verubecestat as a prophylactic treatment for early-stage Alzheimer's disease. The results showed that prophylactic use of verubecestat could reduce amyloid plaque deposition in 5XFAD mice and decrease plasma levels of amyloid beta. However, some side effects were observed within the dosage range, and no improvement in cognitive function was observed.
ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS
(2022)
Review
Chemistry, Multidisciplinary
Derek W. Bartlett, Adam M. Gilbert
Summary: Targeted protein degradation has emerged as an exciting area for therapeutic development in the pharmaceutical industry. This review provides practical insights for understanding the pharmacokinetic and pharmacodynamic properties of protein degraders, and offers a roadmap for their translational development. By using quantitative mathematical frameworks and standard experimental assays, this review highlights the unique characteristics of protein degraders and their potential in drug development.
CHEMICAL SOCIETY REVIEWS
(2022)