Positive Allosteric Modulators (PAMs) of Metabotropic Glutamate Receptor 5 (mGluR5) Attenuate Microglial Activation

Title:Positive Allosteric Modulators (PAMs) of Metabotropic Glutamate Receptor 5 (mGluR5) Attenuate Microglial Activation

Volume: 13 Issue: 4

Author(s): Fengtian Xue, Bogdan A. Stoica, Marie Hanscom, Shruti V. Kabadi and Alan I. Faden

Affiliation:

Keywords: Metabotropic glutamate receptor 5, microglial activation, neuroinflammation, neuroprotection, positive allosteric modulator, traumatic brain injury.

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.

Cite this article as:

Xue Fengtian, Stoica A. Bogdan, Hanscom Marie, Kabadi V. Shruti and Faden I. Alan, Positive Allosteric Modulators (PAMs) of Metabotropic Glutamate Receptor 5 (mGluR5) Attenuate Microglial Activation, CNS & Neurological Disorders - Drug Targets 2014; 13 (4) . https://dx.doi.org/10.2174/18715273113126660199