Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 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.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Balzulat Annika, Zhu W Felix, Flauaus Cathrin, Hernandez-Olmos Victor, Heering Jan, Sethumadhavan Sunesh, Dubiel Mariam, Frank Annika, Menge Amelie, Hebchen Maureen, Metzner Katharina, Lu Ruirui, Lukowski Robert, Ruth Peter, Knapp Stefan, Müller Susanne, Steinhilber Dieter, Hänelt Inga, Stark Holger, Proschak Ewgenij, Schmidtko Achim
Аннотация
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.