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

• Published in: Biochemical and biophysical research communications 2024-08, Vol.721, p.150126, Article 150126
• Main Authors: Kamei, Tatsuya, Kudo, Takehiro, Yamane, Hana, Ishibashi, Fumiaki, Takada, Yoshinori, Honda, Shigeyuki, Maezawa, Yasuyo, Ikeda, Kazuhito, Oyamada, Yoshihiro
• Format: Article
• Language: English
• Subjects: Electrophysiology; Nav1.7 voltage-gated sodium channel; Nav1.8 voltage-gated sodium channel; Nav1.9 voltage-gated sodium channel; Neuropathic pain; Sodium channel blockers
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.150126

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. •Selective inhibition of Nav1.7, Nav1.8, and Nav1.9 by a clinical compound ANP-230.•Tonic block mode of action without state- and use-dependency.•Depolarizing shift of activation curve and gating kinetics deceleration observed.•ANP-230 reduces excitability of primary dorsal root ganglion neurons.•ANP-230 has unique and promising electrophysiological properties as an analgesic.