IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-11-22 DOI:10.1124/jpet.124.002273
Min Su, Xiangshuo Ouyang, Ping Zhou, Liying Dong, Liming Shao, KeWei Wang, Yani Liu
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引用次数: 0

摘要

在外周痛觉神经元中大量表达的 NaV1.7 通道的基因功能缺失突变会导致人类先天性疼痛不敏感,这表明选择性抑制该通道可能会带来潜在的疼痛疾病治疗方法。在这项研究中,我们研究了一种新型化合物--5-氯-N-(环丙基磺酰基)-2-氟-4-(2-(8-(呋喃-2-基甲基)-8-氮杂螺[4.5]癸烷-2-基)乙氧基)苯甲酰胺(QLS-278),它能抑制 NaV1.7 通道并表现出抗痛活性。化合物 QLS-278 对稳定表达在 HEK293 细胞中的 NaV1.7 通道的大电流具有失活和浓度依赖性抑制作用,IC50 为 1.2 ± 0.2 μM。QLS-278 会导致通道失活发生超极化转变,并延迟失活恢复,但对电压依赖性激活没有明显影响。在小鼠背根神经节神经元中,QLS-278 可抑制本地河豚毒素敏感的 NaV 电流,并降低神经元的搏动。此外,QLS-278 还能剂量依赖性地缓解神经损伤引起的神经病理性疼痛和福尔马林引起的炎症性疼痛,而不会明显改变小鼠的自发运动活动。因此,我们发现的新型化合物 QLS-278 在慢性疼痛治疗方面可能具有发展潜力。意义声明:QLS-278是一种新型电压门控钠NaV1.7通道阻断剂,它能抑制原生河豚毒素敏感性Na+电流,减少背根神经节感觉神经元的动作电位跃动。QLS-278 还在小鼠疼痛模型中表现出抗痛活性,显示出开发慢性疼痛治疗药物的潜力。
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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.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
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.
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