Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGluR5) attenuate microglial activation.

Abstract

Traumatic brain injury causes progressive neurodegeneration associated with chronic microglial activation. Recent studies show that neurodegeneration and neuroinflammation after traumatic brain injury can be inhibited as late as one month in animals by the activation of the metabotropic glutamate receptor 5 in microglia using (RS)-2-chloro-5- hydroxy-phenylglycine. However, the therapeutic potential of this agonist is limited due to its relatively weak potency and brain permeability. To address such concerns, we evaluated the anti-inflammatory activities of several positive allosteric modulators using various in vitro assays, and found that 3,3'-difluorobenzaldazine, 3-cyano-N-(1,3-diphenyl-1H-pyrazol- 5-yl)benzamide and 4-nitro-N-(1-(2-fluorophenyl)-3-phenyl-1H-pyrazol-5-yl)benzamide showed significantly improved potency which makes them potential lead compounds for further development of positive allosteric modulators for the treatment of traumatic brain injury.

• Authors: Fengtian Xue, Bogdan A Stoica, Marie Hanscom, Shruti V Kabadi, Alan I Faden
• Journal: CNS & neurological disorders drug targets (CNS Neurol Disord Drug Targets) Vol. 13 Issue 4 Pg. 558-66 ( 2014) ISSN: 1996-3181 [Electronic] United Arab Emirates
• PMID: 24168364 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Benzamides
• Excitatory Amino Acid Agents
• Lipopolysaccharides
• Neuroprotective Agents
• Receptor, Metabotropic Glutamate 5
• Tumor Necrosis Factor-alpha
• Nitric Oxide
• Interferon-gamma

Topics

• Allosteric Regulation
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Benzamides (pharmacology)
• Brain Injuries (drug therapy)
• Cell Line
• Cells, Cultured
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Agents (pharmacology)
• Interferon-gamma (metabolism)
• Lipopolysaccharides
• Mice
• Microglia (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Nitric Oxide (metabolism)
• Rats, Sprague-Dawley
• Receptor, Metabotropic Glutamate 5 (metabolism)
• Time Factors
• Tumor Necrosis Factor-alpha (metabolism)