Advanced Science (Apr 2024)

Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine‐Independent and Chronic Itch

  • Annika Balzulat,
  • W. Felix Zhu,
  • Cathrin Flauaus,
  • Victor Hernandez‐Olmos,
  • Jan Heering,
  • Sunesh Sethumadhavan,
  • Mariam Dubiel,
  • Annika Frank,
  • Amelie Menge,
  • Maureen Hebchen,
  • Katharina Metzner,
  • Ruirui Lu,
  • Robert Lukowski,
  • Peter Ruth,
  • Stefan Knapp,
  • Susanne Müller,
  • Dieter Steinhilber,
  • Inga Hänelt,
  • Holger Stark,
  • Ewgenij Proschak,
  • Achim Schmidtko

DOI
https://doi.org/10.1002/advs.202307237
Journal volume & issue
Vol. 11, no. 15
pp. n/a – n/a

Abstract

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Abstract Various disorders are accompanied by histamine‐independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, KNa1.1), a potassium channel highly expressed in itch‐sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack‐activating antipsychotic drug, loxapine, a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles is designed that enables to validate Slack as a pharmacological target in vivo. One of these new Slack activators, compound 6, exhibits negligible dopamine D2 and D3 receptor binding, unlike loxapine. Notably, compound 6 displays potent on‐target antipruritic activity in multiple mouse models of acute histamine‐independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack.

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