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
Diagnosis and treatment of central nervous system infectious diseases
Infectious diseases of the central nervous system (CNS) can be divided into bacterial, tuberculous, viral, fungal, parasitic infections, etc. Early etiological treatment is often the most crucial means to reduce the mortality rate of patients with central nervous system infections, reduce complications and sequelae, and improve prognosis. The initial clinical ...read more
Techniques of Drug Repurposing: Delivering a new life to Herbs & Drugs
Of late, with the adaptation of innovative approaches and integration of advancements made towards medical sciences as well as the availability of a wide range of tools; several therapeutic challenges are being translated into viable clinical solutions, with a high degree of efficacy, safety, and selectivity. With a better understanding ...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
-
Depression in Coronary Heart Disease Patients: Etiological and Screening Issues
Current Psychiatry Reviews Cardiovascular Risk Factors, Metabolic Complications, & the Natural Course of CKD in Children
Current Hypertension Reviews Commentary: (Research Highlights: “MiRNAcles” in Brain)
CNS & Neurological Disorders - Drug Targets New Trends in the Treatment of Schizophrenia
CNS & Neurological Disorders - Drug Targets Momordica balsamina: A Medicinal and Neutraceutical Plant for Health Care Management
Current Pharmaceutical Biotechnology Suggestion and Pain in Migraine: A Study by Laser Evoked Potentials
CNS & Neurological Disorders - Drug Targets “Speed” Warps Time: Methamphetamines Interactive Roles in Drug Abuse, Habit Formation, and the Biological Clocks of Circadian and Interval Timing
Current Drug Abuse Reviews Cocaine Dependence and Stroke: Pathogenesis and Management
Current Neurovascular Research Lipid-Based Nanocarriers for CNS-Targeted Drug Delivery
Recent Patents on CNS Drug Discovery (Discontinued) Role of Hydrogen Sulfide and Polysulfides in Neurological Diseases: Focus on Protein S-Persulfidation
Current Neuropharmacology Is Time to Change to Halogenated Drugs in Cardiac Surgery, What do we have to do with Propofol?
Current Pharmaceutical Design Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential
Current Pharmaceutical Design Role of Cardiolipin in Mitochondrial Diseases and Apoptosis
Current Medicinal Chemistry Neuroprotective Efficacy of the Peroxisome Proliferator-Activated Receptor-γ Ligand in Chronic Cerebral Hypoperfusion
Current Neurovascular Research Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease
Current Alzheimer Research Biological Basis of Ageing, Age-related Diseases and Interventions
Current Pharmacogenomics and Personalized Medicine Protein Modification by β-N-Acetyl Glucosamine (O-GlcNAc) in Insulin Signaling and Insulin Resistance
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Current Approaches for Drug Delivery to Central Nervous System
Current Drug Delivery QSAR Study on a Series of Aryl Carboxylic Acid Amide Derivatives as Potential Inhibitors of Dihydroorotate Dehydrogenase (DHODH)
Medicinal Chemistry The Orvinols and Related Opioids - High Affinity Ligands with Diverse Efficacy Profiles
Current Pharmaceutical Design