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, Wenyong Zhu, Cathrin Flauaus, Víctor Hernández‐Olmos, Jan Heering, Sunesh Sethumadhavan, Mariam Dubiel, Annika Frank, Amelie Menge, Maureen Hebchen, Katharina Metzner, Ruirui Lu, Robert Łukowski, Peter Ruth, Stefan Knapp, Susanne Müller, Dieter Steinhilber, Inga Hänelt, Holger Stark, Ewgenij Proschak, Achim Schmidtko
Abstract
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, K Na 1.1), 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 D 2 and D 3 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.