In Vitro Inhibition of Voltage-Dependent Sodium Currents by the Antifungal Drug Amorolfine.

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Tác giả: Philip R Effraim, Mohammad-Reza Ghovanloo, Sidharth Tyagi, Stephen G Waxman

Ngôn ngữ: eng

Ký hiệu phân loại: 992 [Unassigned]

Thông tin xuất bản: United States : The Journal of biological chemistry , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 718985

Voltage-gated sodium (Nav) channels are critical for electrical signaling, and their pharmacological modulation can be leveraged for the development of therapeutic agents targeting various disorders. The local anesthetic (LA) site on Nav channels is particularly important, as it is a common target for many clinically used inhibitors, including anticonvulsants and antiarrhythmics. Our goal was to identify novel Nav channel inhibitors by leveraging physicochemical criteria, focusing on potential LA site binding candidates. We identified amorolfine (AMF), a phenyl-propyl morpholine derivative, as a putative modulator. Our results demonstrate that AMF acts as a state-dependent inhibitor of Nav channels, with a ∼30-fold preference for inactivated states. It stabilizes channel inactivation and prevents channel from conducting, driven through its stabilization of inactivation. These findings suggest that AMF represents a new compound that inhibits Nav channels, offering insights into the development of future therapeutic agents targeting Nav and potentially other ion channels.
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