title: 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.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Stoica
authors.forename: Marie
authors.initials: M
authors.lastname: Hanscom
authors.forename: Shruti V
authors.initials: SV
authors.lastname: Kabadi
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201, USA. fxue@rx.umaryland.edu.
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001930:Brain Injuries / Q000188:drug therapy; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001549:Benzamides; D018683:Excitatory Amino Acid Agents; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D064529:Receptor, Metabotropic Glutamate 5; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma