Abstract
An assay to detect the on-target effects of mGlu2/3 receptor antagonists in vivo would be valuable in guiding dosing regimens for the exploration of biological effects of potential therapeutic import. Multiple approaches involving blockade of mGlu2/3 receptor agoinist-driven behavioral effects in mice and rats were investigated. Most of these methods failed to provide a useful method of detection of antagonists in vivo (e.g., locomotor activity). In contrast, the mGlu2/3 receptor agonist LY379268 produced dose-dependent increases in body temperature of mice. The hyperthermic effects of LY379268 was abolished in mGlu2 and in mGlu2/3 receptor null mice but not in mGlu3 null mice. Hyperthermia was not produced by an mGlu8 receptor agonist. Agonist-induced hyperthermia was prevented in a dosedependent manner by structurally-distinct mGlu2/3 receptor antagonists. The blockade was stereo-specific. Moreover, this biological readout was responsive to both orthosteric and to negative allosteric modulators of mGlu2/3 receptors. Antagonism of agonist-induced hyperthermia predicted antidepressant-like efficacy in the mouse forced swim test. As with the hyperthermic response, the antidepressant-like effects of mGlu2/3 receptor antagonists were shown to be due to mGlu2 and not to mGlu3 or mGlu8 receptors through the use of receptor knock-out mice. The ability to rapidly assess ontarget activity of mGlu2/3 receptor antagonists enables determination of parameters for setting efficacy doses in vivo. In turn, efficacy-related data in the preclinical laboratory can help to set expectations of therapeutic potential and dosing in humans.
Keywords: mGlu2/3 receptor, LY341495, MGS0039, LY379268, hyperthermia, forced-swim, mouse.
CNS & Neurological Disorders - Drug Targets
Title:mGlu2/3 Agonist-Induced Hyperthermia: An In Vivo Assay for Detection of mGlu2/3 Receptor Antagonism and its Relation to Antidepressant-Like Efficacy in Mice
Volume: 12 Issue: 5
Author(s): S.D. Gleason, X. Li, I.A. Smith, J.D. Ephlin, X-S. Wang, B. A. Heinz, J.H. Carter, M. Baez, J. Yu, D.M. Bender and J.M. Witkin
Affiliation:
Keywords: mGlu2/3 receptor, LY341495, MGS0039, LY379268, hyperthermia, forced-swim, mouse.
Abstract: An assay to detect the on-target effects of mGlu2/3 receptor antagonists in vivo would be valuable in guiding dosing regimens for the exploration of biological effects of potential therapeutic import. Multiple approaches involving blockade of mGlu2/3 receptor agoinist-driven behavioral effects in mice and rats were investigated. Most of these methods failed to provide a useful method of detection of antagonists in vivo (e.g., locomotor activity). In contrast, the mGlu2/3 receptor agonist LY379268 produced dose-dependent increases in body temperature of mice. The hyperthermic effects of LY379268 was abolished in mGlu2 and in mGlu2/3 receptor null mice but not in mGlu3 null mice. Hyperthermia was not produced by an mGlu8 receptor agonist. Agonist-induced hyperthermia was prevented in a dosedependent manner by structurally-distinct mGlu2/3 receptor antagonists. The blockade was stereo-specific. Moreover, this biological readout was responsive to both orthosteric and to negative allosteric modulators of mGlu2/3 receptors. Antagonism of agonist-induced hyperthermia predicted antidepressant-like efficacy in the mouse forced swim test. As with the hyperthermic response, the antidepressant-like effects of mGlu2/3 receptor antagonists were shown to be due to mGlu2 and not to mGlu3 or mGlu8 receptors through the use of receptor knock-out mice. The ability to rapidly assess ontarget activity of mGlu2/3 receptor antagonists enables determination of parameters for setting efficacy doses in vivo. In turn, efficacy-related data in the preclinical laboratory can help to set expectations of therapeutic potential and dosing in humans.
Export Options
About this article
Cite this article as:
Gleason S.D., Li X., Smith I.A., Ephlin J.D., Wang X-S., Heinz B. A., Carter J.H., Baez M., Yu J., Bender D.M. and Witkin J.M., mGlu2/3 Agonist-Induced Hyperthermia: An In Vivo Assay for Detection of mGlu2/3 Receptor Antagonism and its Relation to Antidepressant-Like Efficacy in Mice, CNS & Neurological Disorders - Drug Targets 2013; 12 (5) . https://dx.doi.org/10.2174/18715273113129990079
DOI https://dx.doi.org/10.2174/18715273113129990079 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Novel Treatments in Subarachnoid Hemorrhage
The current landscape of therapeutic strategies for subarachnoid hemorrhage (SAH), a significant adverse neurological event commonly resulting from the rupture of intracranial aneurysms, is rapidly evolving. Through an in-depth exploration of the natural history of SAH, historical treatment approaches, and emerging management modalities, the present work aims to provide a ...read more
Role of glial cells in autism spectrum disorder: Molecular mechanism and therapeutic approaches
Emerging evidence suggests that glial cells may play a pivotal role in neuroanatomical and behavioral changes found in autism spectrum disorder (ASD). Many individuals with ASD experience a neuro-immune system abnormalities throughout life, which implicates a potential role of microglia in the pathogenesis of ASD. Dysfunctional astrocytes and oligodendrocytes were ...read more
Trends and perspectives in the rational management of CNS disorders
Central nervous system (CNS) diseases enforce a significant global health burden, driving ongoing efforts to improve our understanding and effectiveness of therapy. This issue investigates current advances in the discipline, focusing on the understanding as well as therapeutic handling of various CNS diseases. The issue covers a variety of diseases, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Infertile Women's Perceptions of Infertility: A Phenomenological Study
Based on Metaphor Analysis
Current Women`s Health Reviews Protein Modification by Peroxidative Products of Polyunsaturated Fatty Acids
Current Proteomics Targeting Toll-like Receptors in Autoimmunity
Current Drug Targets Role of Topological, Electronic, Geometrical, Constitutional and Quantum Chemical Based Descriptors in QSAR: mPGES-1 as a Case Study
Current Topics in Medicinal Chemistry Synthesis of a Novel Curcumin Derivative as a Potential Imaging Probe in Alzheimer’s Disease Imaging
Current Alzheimer Research Chemical Modifications of Ketoprofen (NSAID) in Search of Better Lead Compounds: A Review of Literature From 2004-2016
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Ligand- and Protein-Based Modeling Studies of the Inhibitors of Human Cytochrome P450 2D6 and a Virtual Screening for Potential Inhibitors from the Chinese Herbal Medicine, Scutellaria baicalensis (Huangqin,Baikal Skullcap)
Combinatorial Chemistry & High Throughput Screening Role of Brassinosteroid in Plant Adaptation to Abiotic Stresses and its Interplay with Other Hormones
Current Protein & Peptide Science The Glycogen Synthase Kinase-3 in the Regulation of Ion Channels and Cellular Carriers
Current Medicinal Chemistry Oral Disintegrating Tablets – An Updated Patent Perspective
Recent Patents on Drug Delivery & Formulation The Role of EGFR-Met Interactions in the Pathogenesis of Glioblastoma and Resistance to Treatment
Current Cancer Drug Targets The Discovery of Novel Chemotypes of p38 Kinase Inhibitors
Current Topics in Medicinal Chemistry New Approaches to Structure-Based Discovery of Dengue Protease Inhibitors
Infectious Disorders - Drug Targets IDO and Clinical Conditions Associated with Depressive Symptoms
Current Drug Metabolism Measurement Matters in Evaluating Youth Antidepressant Effectiveness
Adolescent Psychiatry Transmodulation of Dopaminergic Signaling to Mitigate Hypodopminergia and Pharmaceutical Opioid-induced Hyperalgesia
Current Psychopharmacology Editorial [Hot Topic:Perspective on Mild Cognitive Impairment (MCI) (Guest Editor: Bernardino Ghetti)]
Current Alzheimer Research Recent Advances in the Rationale Design of GPER Ligands
Current Medicinal Chemistry Nitric Oxide and Major Depressive Disorder: Pathophysiology and Treatment Implications
Current Molecular Medicine Vitamins and Cognition: A Nutrigenomics Perspective
Current Nutrition & Food Science