Discovery of a new activator of Slack potassium channels with robust efficacy in models of histamine-independent and chronic itch

Balzulat, A.; Zhu, W. F.; Flauaus, C.; Hernandez-Olmos, V.; Heering, J.; Sethumadhavan, S.; Dubiel, M.; Frank, A.; Menge, A.; Hebchen, M.; Metzner, K.; Lu, R.; Lukowski, R.; Ruth, P.; Knapp, S.; Mueller, S.; Steinhilber, D.; Haenelt, I.; Stark, H.; Proschak, E.; Schmidtko, A.

doi:10.1101/2023.10.05.560997

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bioRxiv · 10.1101/2023.10.05.560997

Discovery of a new activator of Slack potassium channels with robust efficacy in models of histamine-independent and chronic itch

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Abstract

Various disorders are accompanied by histamine-independent itching, which is often resistant to the currently available therapies. In this study, we hypothesized that 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, we designed a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles that enabled us to validate Slack as a pharmacological target in vivo. One of these new Slack activators, compound 6, exhibited negligible dopamine D2 and D3 receptor binding, unlike loxapine. We found that compound 6 displayed 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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Balzulat, A., Zhu, W. F., Flauaus, C., Hernandez-Olmos, V., Heering, J., Sethumadhavan, S., Dubiel, M., Frank, A., Menge, A., Hebchen, M., Metzner, K., Lu, R., Lukowski, R., Ruth, P., Knapp, S., Mueller, S., Steinhilber, D., Haenelt, I., Stark, H., Proschak, E., Schmidtko, A.. 2023-10-06. Discovery of a new activator of Slack potassium channels with robust efficacy in models of histamine-independent and chronic itch. https://doi.org/10.1101/2023.10.05.560997

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