Unique electrophysiological property of a novel Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker, ANP-230.

Autor: Kamei T; Pharmacology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan; Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co., Ltd., Kobe, 650-0047, Japan. Electronic address: tatsuya.kamei@sumitomo-pharma.co.jp., Kudo T; Pharmacology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan., Yamane H; Pharmacology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan; Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co., Ltd., Kobe, 650-0047, Japan., Ishibashi F; Pharmacology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan; Platform Technology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan., Takada Y; Pharmacology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan; Global Corporate Strategy, Sumitomo Pharma Co., Ltd., Tokyo, 104-8356, Japan., Honda S; Pharmacology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan; Sumika Chemical Analysis Service, Ltd., Osaka, 554-0022, Japan., Maezawa Y; Pharmacology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan., Ikeda K; Pharmacology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan; Platform Technology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan., Oyamada Y; Pharmacology Research Unit, Research Division, Sumitomo Pharma Co., Ltd., Osaka, 554-0022, Japan; AlphaNavi Pharma Inc., Osaka, 564-0053, Japan.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Aug 20; Vol. 721, pp. 150126. Date of Electronic Publication: 2024 May 14.
DOI: 10.1016/j.bbrc.2024.150126
Abstrakt: Voltage-gated sodium channel subtypes, Nav1.7, Nav1.8, and Nav1.9 are predominantly expressed in peripheral sensory neurons. Recent genetic studies have revealed that they are involved in pathological pain processing and that the blockade of Nav1.7, Nav1.8, or Nav1.9 will become a promising pharmacotherapy especially for neuropathic pain. A growing number of drug discovery programs have targeted either of the subtypes to obtain a selective inhibitor which can provide pain relief without affecting the cardiovascular and central nervous systems, though none of them has been approved yet. Here we describe the in vitro characteristics of ANP-230, a novel sodium channel blocker under clinical development. Surprisingly, ANP-230 was shown to block three pain-related subtypes, human Nav1.7, Nav1.8, and Nav1.9 with similar potency, but had only low inhibitory activity to human cardiac Nav1.5 channel and rat central Nav channels. The voltage clamp experiments using different step pulse protocols revealed that ANP-230 had a "tonic block" mode of action without state- and use-dependency. In addition, ANP-230 caused a depolarizing shift of the activation curve and decelerated gating kinetics in human Nav1.7-stably expressing cells. The depolarizing shift of activation curve was commonly observed in human Nav1.8-stably expressing cells as well as rat dorsal root ganglion neurons. These data suggested a quite unique mechanism of Nav channel inhibition by ANP-230. Finally, ANP-230 reduced excitability of rat dorsal root ganglion neurons in a concentration dependent manner. Collectively, these promising results indicate that ANP-230 could be a potent drug for neuropathic pain.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tatsuya Kamei reports financial support was provided by Sumitomo Pharma Co Ltd. Takehiro Kudo reports financial support was provided by Sumitomo Pharma Co Ltd. Hana Yamane reports financial support was provided by Sumitomo Pharma Co Ltd. Fumiaki Ishibashi reports financial support was provided by Sumitomo Pharma Co Ltd. Yoshinori Takada reports financial support was provided by Sumitomo Pharma Co Ltd. Shigeyuki Honda reports financial support was provided by Sumitomo Pharma Co Ltd. Yasuyo Maezawa reports financial support was provided by Sumitomo Pharma Co Ltd. Kazuhito Ikeda reports financial support was provided by Sumitomo Pharma Co Ltd. Yoshihiro Oyamada reports financial support was provided by Sumitomo Pharma Co Ltd. Yoshihiro Oyamada reports a relationship with AlphaNavi Pharma Inc that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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