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Neurological disorders

Chloride extrusion alleviates neuropathic pain

Nature Reviews Drug Discovery volume 12, page 906 (2013)Cite this article

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The maintenance of low Cl− concentrations is essential for postsynaptic inhibition, and Cl− extrusion is controlled by a family of cation chloride cotransporters including KCC2. KCC2 is particularly attractive as a drug target as its expression is strictly limited to the CNS.

To identify compounds that increase Cl− efflux via KCC2, the authors developed a fluorometric assay using a Cl−-sensitive indicator in a neuronal cell line (NG-108) that has low KCC2 activity and mimics the pathophysiological situation in neuropathic pain. A high-throughput screen of 92,500 drug-like compounds, followed by a lead optimization campaign, led to the development of CLP257, a small molecule that achieved a maximal Cl− reduction of 40% in NG-108 cells.

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References

  1. Gagnon, M. et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nature Med. http://dx.doi.org/10.1038/nm.3356 (2013)

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  1. Alexandra Flemming
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Flemming, A. Chloride extrusion alleviates neuropathic pain. Nat Rev Drug Discov 12, 906 (2013). https://doi.org/10.1038/nrd4183

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