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Here, it is reported that the pharmacological activation of Slack (Kcnt1, K\n                    <jats:sub>Na<\/jats:sub>\n                    1.1), a potassium channel highly expressed in itch\u2010sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack\u2010activating 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\n                    <jats:sub>2<\/jats:sub>\n                    and D\n                    <jats:sub>3<\/jats:sub>\n                    receptor binding, unlike loxapine. Notably, compound 6 displays potent on\u2010target antipruritic activity in multiple mouse models of acute histamine\u2010independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack.\n                  <\/jats:p>","DOI":"10.1002\/advs.202307237","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T21:19:44Z","timestamp":1707859184000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine\u2010Independent and Chronic Itch"],"prefix":"10.1002","volume":"11","author":[{"given":"Annika","family":"Balzulat","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Clinical Pharmacy Goethe University Frankfurt  Max\u2010von\u2010Laue\u2010Str. 9 60438 Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. 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