ArticleBiological psychiatry2013
Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity.
Article in Biological psychiatry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 106 citations in OpenAlex.
- Unraveling allosteric signaling of G protein-coupled receptors (GPCRs) by single-molecule fluorescence.Biophysical reviews · 2026Review
- Botulinum Toxin Type A as a Therapeutic Agent in Epilepsy: Attenuation of Neuronal Ferroptosis and Cognitive Dysfunction.Brain and behavior · 2025Article
- The anti-dyskinetic effect of the clinic-ready mGluRNaunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Conformational diversity in class C GPCR positive allosteric modulation.Nature communications · 2025Article
- Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.Pharmacological reviews · 2022Review
- Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia.Molecular pharmacology · 2022Review
- Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state.Nature communications · 2021Article
- Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.Cell reports · 2021Article
- Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain.Frontiers in molecular biosciences · 2020Article
- Article
- Targeting Muscarinic Acetylcholine Receptors for the Treatment of Psychiatric and Neurological Disorders.Trends in pharmacological sciences · 2019Review
- Article
- Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.Journal of medicinal chemistry · 2019Review
- Targeting mGlu Receptors for Optimization of Antipsychotic Activity and Disease-Modifying Effect in Schizophrenia.Frontiers in psychiatry · 2019Review
- PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems.ACS chemical neuroscience · 2018Article
- Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4.Bioorganic & medicinal chemistry · 2018Article
- Metabotropic Glutamatergic Receptor 5 and Stress Disorders: Knowledge Gained From Receptor Imaging Studies.Biological psychiatry · 2018Review
- MNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2018Article
- Differential Pharmacology and Binding of mGluMolecular pharmacology · 2018Article
- Direct coupling of detergent purified human mGluScientific reports · 2018Article
Corrections and comments
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Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundMetabotropic glutamate receptor subtype 5 (mGlu5) activators have emerged as a novel approach to the treatment of schizophrenia. Positive allosteric modulators (PAMs) of mGlu5 have generated tremendous excitement and fueled major drug discovery efforts. Although mGlu5 PAMs have robust efficacy in preclinical models of schizophrenia, preliminary reports suggest that these compounds may induce seizure activity. Prototypical mGlu5 PAMs do not activate mGlu5 directly but selectively potentiate activation of mGlu5 by glutamate. This mechanism may be critical to maintaining normal activity-dependence of mGlu5 activation and achieving optimal in vivo effects.
methodsUsing specially engineered mGlu5 cell lines incorporating point mutations within the allosteric and orthosteric binding sites, as well as brain slice electrophysiology and in vivo electroencephalography and behavioral pharmacology, we found that some mGlu5 PAMs have intrinsic allosteric agonist activity in the absence of glutamate.
resultsBoth in vitro mutagenesis and in vivo pharmacology studies demonstrate that VU0422465 is an agonist PAM that induces epileptiform activity and behavioral convulsions in rodents. In contrast, VU0361747, an mGlu5 PAMs optimized to eliminate allosteric agonist activity, has robust in vivo efficacy and does not induce adverse effects at doses that yield high brain concentrations.
conclusionsLoss of the absolute dependence of mGlu5 PAMs on glutamate release for their activity can lead to severe adverse effects. The finding that closely related mGlu5 PAMs can differ in their intrinsic agonist activity provides critical new insights that is essential for advancing these molecules through clinical development for treatment of schizophrenia.
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