Positive Allosteric Modulators (PAMs) of Metabotropic Glutamate Receptor 5 (mGluR5) Attenuate Microglial Activation
Fengtian Xue, Bogdan A. Stoica, Marie Hanscom, Shruti V. Kabadi and Alan I. Faden
Affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201, USA.
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.
Keywords: Metabotropic glutamate receptor 5, microglial activation, neuroinflammation, neuroprotection, positive allosteric
modulator, traumatic brain injury.
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