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
em 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.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Bloqueadores dos Canais de Sódio
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Canal de Sódio Disparado por Voltagem NAV1.7
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Analgésicos
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Neuralgia
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Canadá