Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine-Independent and Chronic Itch.
Adv Sci (Weinh)
; 11(15): e2307237, 2024 Apr.
Article
in En
| MEDLINE
| ID: mdl-38350720
ABSTRACT
Various disorders are accompanied by histamine-independent itching, which is often resistant to the currently available therapies. Here, it is reported that the 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, 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 D2 and D3 receptor binding, unlike loxapine. Notably, compound 6 displays 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pruritus
/
Potassium Channels
Limits:
Animals
Language:
En
Journal:
Adv Sci (Weinh)
Year:
2024
Document type:
Article
Affiliation country:
Alemania
Country of publication:
Alemania