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

被引：21

作者：

Xue, Fengtian ^{[1
,2
]}

Stoica, Bogdan A. ^{[1
]}

Hanscom, Marie ^{[1
]}

Kabadi, Shruti V. ^{[1
]}

Faden, Alan I. ^{[1
]}

机构：

[1] Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA

[2] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA

来源：

CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS | 2014年 / 13卷 / 04期

关键词：

Metabotropic glutamate receptor 5; microglial activation; neuroinflammation; neuroprotection; positive allosteric modulator; traumatic brain injury; PROTEIN-COUPLED RECEPTORS; IN-VIVO; BRAIN-INJURY; DRUG DEVELOPMENT; CELL-DEATH; RAT; DISCOVERY; VITRO; SUBTYPE-5; APOPTOSIS;

D O I：

10.2174/18715273113126660199

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：558 / 566

页数：9

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