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.
Keywords: Metabotropic glutamate receptor 5, microglial activation, neuroinflammation, neuroprotection, positive allosteric modulator, traumatic brain injury.
CNS & Neurological Disorders - Drug Targets
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.
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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
DOI https://dx.doi.org/10.2174/18715273113126660199 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
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