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
en 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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Prurito
/
Canales de Potasio
Límite:
Animals
Idioma:
En
Revista:
Adv Sci (Weinh)
Año:
2024
Tipo del documento:
Article
País de afiliación:
Alemania