Targeting Slack (Kcnt1) potassium channels for treatment of histamine-independent itch

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