Discovery of a new activator of Slack potassium channels with robust efficacy in models of histamine-independent and chronic itch
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (Arcadia Science)
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 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 D 2 and D 3 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.
Article activity feed
-
Neither mechanical nor thermal sensitivity was altered by compound 6 compared to the vehicle control
Huang, F., et al. 2013 showed that in Slack knockout rats, the knockouts were more sensitive to heat stimuli than control rats at 50oC. Your methods mention a infrared intensity setting of 25. What temperature corresponds to a setting of 25?
-
These findings are important because they indicate that Slack activators can reduce existing itching.
I'm curious if the antipruritic activity of compound 6 was long lasting. Did you examine if hours or days after administration of compound 6, the mice continued to show a reduction in scratching vs. control in your chronic itch models?
-
Importantly, we found that systemic treatment of mice with compound 6 (3, 10, or 30 mg/kg i.p.) 15 min prior to subcutaneous (s.c.) injection of chloroquine into the nape of the neck ameliorated scratching behavior in a dose-dependent manner
This is really nice dose-dependent reduction in scratching! I'm curious how you choose the timing for compound 6 administration? And did you try subcutaneous injections of compound 6 as well as systemic administration? I'm wondering if s.c. injections may help reduce potential undesirable off-target effects of compound 6 when compared to systemic administration.
-
