Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain.
Cell Rep
; 24(12): 3133-3145, 2018 09 18.
Article
en En
| MEDLINE
| ID: mdl-30231997
ABSTRACT
Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sulfonamidas
/
Bloqueadores de los Canales de Sodio
/
Canal de Sodio Activado por Voltaje NAV1.7
/
Analgésicos
/
Neuralgia
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Rep
Año:
2018
Tipo del documento:
Article
País de afiliación:
Canadá