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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 6, 2023

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, K Na 1.1), a potassium channel highly expressed in itch-sensitive sensory neurons, has therapeutic potential for treatment itching. Based on Slack-activating antipsychotic drug, loxapine, designed series new derivatives with improved pharmacodynamic and pharmacokinetic profiles enabled us validate as target vivo . One these activators, compound 6, exhibited negligible dopamine D 2 3 receptor binding, unlike loxapine. We found 6 displayed potent on-target antipruritic activity multiple mouse models acute chronic itch without motor side effects. These properties make lead molecule development therapies targeting Slack.

Язык: Английский

Druggable Targets and Compounds with Both Antinociceptive and Antipruritic Effects

Pharmaceuticals, Год журнала: 2022, Номер 15(7), С. 892 - 892

Опубликована: Июль 19, 2022

Pain and itch are both important manifestations of various disorders, such as herpes zoster, atopic dermatitis, psoriasis. Growing evidence suggests that sensations have shared mediators, overlapping neural circuitry, similarities in sensitization processes. In fact, pain coexist some disorders. Determining pharmaceutical agents targets for treating concurrently is scientific clinical relevance. Here we review the neurobiology discuss well novel compounds effective concurrent treatment these sensations.

Язык: Английский