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Kinetic Analysis of Membrane Potential Dye Response to NaV1.7 Channel Activation Identifies Antagonists with Pharmacological Selectivity against NaV1.5.
Finley, Michael; Cassaday, Jason; Kreamer, Tony; Li, Xinnian; Solly, Kelli; O'Donnell, Greg; Clements, Michelle; Converso, Antonella; Cook, Sean; Daley, Chris; Kraus, Richard; Lai, Ming-Tain; Layton, Mark; Lemaire, Wei; Staas, Donnette; Wang, Jixin.
Afiliación
  • Finley M; Merck Research Labs, Screening and Protein Sciences, North Wales, PA, USA michael.finley@merck.com.
  • Cassaday J; Merck Research Labs, Screening and Protein Sciences, North Wales, PA, USA.
  • Kreamer T; Merck Research Labs, Screening and Protein Sciences, North Wales, PA, USA.
  • Li X; Merck Research Labs, Screening and Protein Sciences, North Wales, PA, USA.
  • Solly K; Merck Research Labs, Screening and Protein Sciences, North Wales, PA, USA.
  • O'Donnell G; Merck Research Labs, Screening and Protein Sciences, North Wales, PA, USA.
  • Clements M; Merck Research Labs, Pharmacology, West Point, PA, USA.
  • Converso A; Merck Research Labs, Chemistry, West Point, PA, USA.
  • Cook S; Merck Research Labs, Pharmacology, West Point, PA, USA CNS Discovery Research, Teva Pharmaceuticals, West Chester, PA, USA.
  • Daley C; Merck Research Labs, Pharmacology, West Point, PA, USA.
  • Kraus R; Merck Research Labs, Pharmacology, West Point, PA, USA.
  • Lai MT; Merck Research Labs, Pharmacology, West Point, PA, USA.
  • Layton M; Merck Research Labs, Chemistry, West Point, PA, USA.
  • Lemaire W; Merck Research Labs, Pharmacology, West Point, PA, USA.
  • Staas D; Merck Research Labs, Chemical Modeling and Informatics, West Point, PA, USA.
  • Wang J; Merck Research Labs, Pharmacology, West Point, PA, USA.
J Biomol Screen ; 21(5): 480-9, 2016 Jun.
Article en En | MEDLINE | ID: mdl-26861708
The NaV1.7 voltage-gated sodium channel is a highly valued target for the treatment of neuropathic pain due to its expression in pain-sensing neurons and human genetic mutations in the gene encoding NaV1.7, resulting in either loss-of-function (e.g., congenital analgesia) or gain-of-function (e.g., paroxysmal extreme pain disorder) pain phenotypes. We exploited existing technologies in a novel manner to identify selective antagonists of NaV1.7. A full-deck high-throughput screen was developed for both NaV1.7 and cardiac NaV1.5 channels using a cell-based membrane potential dye FLIPR assay. In assay development, known local anesthetic site inhibitors produced a decrease in maximal response; however, a subset of compounds exhibited a concentration-dependent delay in the onset of the response with little change in the peak of the response at any concentration. Therefore, two methods of analysis were employed for the screen: one to measure peak response and another to measure area under the curve, which would capture the delay-to-onset phenotype. Although a number of compounds were identified by a selective reduction in peak response in NaV1.7 relative to 1.5, the AUC measurement and a subsequent refinement of this measurement were able to differentiate compounds with NaV1.7 pharmacological selectivity over NaV1.5 as confirmed in electrophysiology.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Ensayos Analíticos de Alto Rendimiento / Canal de Sodio Activado por Voltaje NAV1.5 / Canal de Sodio Activado por Voltaje NAV1.7 / Neuralgia Tipo de estudio: Prognostic_studies Idioma: En Revista: J Biomol Screen Asunto de la revista: BIOLOGIA MOLECULAR Año: 2016 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Ensayos Analíticos de Alto Rendimiento / Canal de Sodio Activado por Voltaje NAV1.5 / Canal de Sodio Activado por Voltaje NAV1.7 / Neuralgia Tipo de estudio: Prognostic_studies Idioma: En Revista: J Biomol Screen Asunto de la revista: BIOLOGIA MOLECULAR Año: 2016 Tipo del documento: Article