P2X7 Antagonists as Potential Therapeutic Agents for the Treatment of CNS Disorders

Chrovian, Christa C.; Rech, Jason C.; Bhattacharya, Anindya; Letavic, Michael A.

doi:10.1016/b978-0-444-63380-4.00002-0

Cited by 59 publications

(49 citation statements)

References 83 publications

(116 reference statements)

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“…30 In addition, release of ATP and activation of purinergic receptors modulate the neuroinflammatory process. 31 Neuroinflammation, the activation of resident inflammatory cells in the brain, contributes to the evolution of the ischemic lesion and to tissue remodeling. Our results show that astrocyte activation is modified in the absence of AQP4, with less intense labeling in the lesion border but a more widespread distribution of GFAP labeling.…”

Section: Discussionmentioning

confidence: 99%

Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice

Hirt

Fukuda

Ambadipudi

et al. 2016

J Cereb Blood Flow Metab

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A hallmark of stroke is water accumulation (edema) resulting from dysregulation of osmotic homeostasis. Brain edema contributes to tissue demise and may lead to increased intracranial pressure and lethal herniation. Currently, there are only limited treatments to prevent edema formation following stroke. Aquaporin 4 (AQP4), a brain water channel, has become a focus of interest for therapeutic approaches targeting edema. At present, there are no pharmacological tools to block AQP4. The role of AQP4 in edema after brain injury remains unclear with conflicting results from studies using AQP4 À/À mice and of AQP4 expression following stroke. Here, we studied AQP4 and its role in edema formation by testing AQP4À/À mice in a model of middle cerebral artery occlusion using novel quantitative MRI water content measurements, histology and behavioral changes as outcome measures. Absence of AQP4 was associated with decreased mortality and increased motor recovery 3 to 14 days after stroke. Behavioral improvement was associated with decreased lesion volume, neuronal cell death and neuroinflammation in AQP4 À/À compared to wild type mice. Our data suggest that the lack of AQP4 confers an overall beneficial role at long term with improved neuronal survival and reduced neuroinflammation, but without a direct effect on edema formation.

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Section: Discussionmentioning

confidence: 99%

Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice

Hirt

Fukuda

Ambadipudi

et al. 2016

J Cereb Blood Flow Metab

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“…[5][6][7] P2X 7 receptor antagonists have been developed as potential pharmaceuticals for the treatment of various diseases including neuroinflammation. [8][9][10] We are interested in biomedical imaging to detect and quantify neuroinflammation, with positron emission tomography (PET) offering the best opportunity for success with development and validation of suitable targeted radioligands. However, an ideal PET radiopharmaceutical is still missing.…”

mentioning

confidence: 99%

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

Gao

Wang

Green

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Abstract-The authentic standards GSK1482160 and its isomer, as well as the radiolabeling precursors desmethyl-GSK1482160 and Boc-protected desmethyl-GSK1482160 were synthesized from L-pyroglutamic acid, methyl L-pyroglutamate and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 27-28% in 3 steps, 58% in 4 steps, 76% in 1 step and 33% in 2 steps, respectively. [11 C]GSK1482160 was prepared from either desmethyl-GSK1482160 or Boc-protected desmethyl-GSK1482160 with [11 C]CH 3 OTf through N-[ 11 C]methylation and isolated by HPLC combined with SPE in 40-50% and 30-40% radiochemical yield, respectively, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/mol with a total synthesis time of ~40-minutes from EOB.

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“…These include Abbott, Actelion, Affectis, AstraZeneca, Evotec, GlaxoSmithKline, Janssen, Johnson and Johnson, Merck, Neurogen, Nissan Chemical, Pfizer, Roche and Schering [92,93]. Because the activation of P2X7 receptors by ATP is a key step in the release of inflammatory cytokines from microglia primed with bacterial lipopolysaccharide [94], P2X receptors have long been considered as possible therapeutic targets in inflammatory pain [95,96].…”

Section: Therapeutic Exploitationmentioning

confidence: 99%

“…P2X7 receptors have been the most intensively investigated and many pharmaceutical companies have synthesized small molecules that are potent and selective blockers of the human receptor [92]. These include Abbott, Actelion, Affectis, AstraZeneca, Evotec, GlaxoSmithKline, Janssen, Johnson and Johnson, Merck, Neurogen, Nissan Chemical, Pfizer, Roche and Schering [92,93].…”

Section: Therapeutic Exploitationmentioning

confidence: 99%