Min Su, Xiangshuo Ouyang, Ping Zhou, Liying Dong, Liming Shao, KeWei Wang, Yani Liu
{"title":"Inhibition of TTX-S Na<sup>+</sup> currents by a novel blocker QLS-278 for antinociception.","authors":"Min Su, Xiangshuo Ouyang, Ping Zhou, Liying Dong, Liming Shao, KeWei Wang, Yani Liu","doi":"10.1124/jpet.124.002273","DOIUrl":null,"url":null,"abstract":"<p><p>Genetic loss-of-function mutations of the Na<sub>V</sub>1.7 channel, abundantly expressed in peripheral nociceptive neurons, cause congenital insensitivity to pain in humans, indicating that selective inhibition of the channel may lead to potential therapy for pain disorders. In this study, we investigated a novel compound, 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(2-(8-(furan-2-ylmethyl)-8-azaspiro [4.5] decan-2-yl) ethoxy) benzamide (QLS-278) that inhibits Na<sub>V</sub>1.7 channels and exhibits antinociceptive activity. Compound QLS-278 exhibits inactivation- and concentration-dependent inhibition of macroscopic currents of Na<sub>V</sub>1.7 channels stably expressed in HEK293 cells with an IC<sub>50</sub> of 1.2 ± 0.2 μM. QLS-278 causes a hyperpolarization shift of the channel inactivation and delays recovery from inactivation, without any noticeable effect on voltage-dependent activation. In mouse dorsal root ganglion neurons, QLS-278 suppresses native tetrodotoxin-sensitive Na<sub>V</sub> currents and also reduces neuronal firings. Moreover, QLS-278 dose-dependently relieves neuropathic pain induced by spared nerve injury and inflammatory pain induced by formalin without significantly altering spontaneous locomotor activity in mice. Therefore, our identification of the novel compound QLS-278 may hold developmental potential in chronic pain treatment. SIGNIFICANCE STATEMENT: QLS-278, a novel voltage-gated sodium Na<sub>V</sub>1.7 channel blocker, inhibits native tetrodotoxin-sensitive Na<sup>+</sup> current and reduces action potential firings in dorsal root ganglion sensory neurons. QLS-278 also exhibits antinociceptive activity in mouse models of pain, demonstrating the potential for the development of a chronic pain treatment.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100030"},"PeriodicalIF":3.1000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Pharmacology and Experimental Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1124/jpet.124.002273","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/22 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Inhibition of TTX-S Na+ currents by a novel blocker QLS-278 for antinociception.
Genetic loss-of-function mutations of the NaV1.7 channel, abundantly expressed in peripheral nociceptive neurons, cause congenital insensitivity to pain in humans, indicating that selective inhibition of the channel may lead to potential therapy for pain disorders. In this study, we investigated a novel compound, 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(2-(8-(furan-2-ylmethyl)-8-azaspiro [4.5] decan-2-yl) ethoxy) benzamide (QLS-278) that inhibits NaV1.7 channels and exhibits antinociceptive activity. Compound QLS-278 exhibits inactivation- and concentration-dependent inhibition of macroscopic currents of NaV1.7 channels stably expressed in HEK293 cells with an IC50 of 1.2 ± 0.2 μM. QLS-278 causes a hyperpolarization shift of the channel inactivation and delays recovery from inactivation, without any noticeable effect on voltage-dependent activation. In mouse dorsal root ganglion neurons, QLS-278 suppresses native tetrodotoxin-sensitive NaV currents and also reduces neuronal firings. Moreover, QLS-278 dose-dependently relieves neuropathic pain induced by spared nerve injury and inflammatory pain induced by formalin without significantly altering spontaneous locomotor activity in mice. Therefore, our identification of the novel compound QLS-278 may hold developmental potential in chronic pain treatment. SIGNIFICANCE STATEMENT: QLS-278, a novel voltage-gated sodium NaV1.7 channel blocker, inhibits native tetrodotoxin-sensitive Na+ current and reduces action potential firings in dorsal root ganglion sensory neurons. QLS-278 also exhibits antinociceptive activity in mouse models of pain, demonstrating the potential for the development of a chronic pain treatment.
期刊介绍:
A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.