更新于：2024-11-01

KCNQ5 x Kv7.3 x Kv7.2 x Kv7.4

更新于：2024-11-01

基本信息

关联

项与 KCNQ5 x Kv7.3 x Kv7.2 x Kv7.4 相关的药物

PF-05020182

靶点

KCNQ5 x Kv7.2 x Kv7.3 x Kv7.4

作用机制

KCNQ5 modulators [+3]

在研机构-

原研机构

Pfizer Inc.

在研适应症-

非在研适应症

癫痫

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 KCNQ5 x Kv7.3 x Kv7.2 x Kv7.4 相关的临床结果

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100 项与 KCNQ5 x Kv7.3 x Kv7.2 x Kv7.4 相关的转化医学

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0 项与 KCNQ5 x Kv7.3 x Kv7.2 x Kv7.4 相关的专利（医药）

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项与 KCNQ5 x Kv7.3 x Kv7.2 x Kv7.4 相关的文献（医药）

2023-01-01·Pharmacology

Inhibition of Kv7/M Channel Currents by Fangchinoline

Article

作者: Wang, Runmeng ; Geng, DanDan ; Zhang, Fan ; Zheng, Rong ; Li, Han ; Jia, Qingzhong ; Liu, Yidong ; Li, Yaning

Introduction: Voltage-gated Kv7/M potassium channels play an essential role in the control of membrane potential and neuronal excitability. Fangchinoline, a bisbenzylisoquinoline alkaloid, displays extensive biological activities including antitumor, anti-inflammatory, and antihypertension effects. In this study, we investigated the effects of fangchinoline on Kv7/M channels. Methods: A perforated whole-cell patch technique was used to record Kv7 currents from HEK293 cells and M-type currents from mouse dorsal root ganglion (DRG) neurons. Results: Fangchinoline inhibited Kv7.2/Kv7.3 currents in a concentration-dependent manner, with an IC50 of 9.5 ± 1.2 μM. Fangchinoline significantly inhibited Kv7.1, Kv7.2, Kv7.3, Kv7.4, and Kv7.3/Kv7.5 channels without selective effects. Furthermore, fangchinoline significantly slowed the activation of Kv7.1-Kv7.5 channels and inhibited native M-channel currents of DRG neurons. Conclusion: Taken together, our findings indicate that fangchinoline concentration-dependently inhibited Kv7/M channel currents.

2018-10-01·Molecular Pharmacology3区 · 医学

Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

3区 · 医学

Article

作者: Manville, Rían W ; Abbott, Geoffrey W

Synthetic gabapentinoids, exemplified by gapapentin and pregabalin, are in extensive clinical use for indications including epilepsy, neuropathic pain, anxiety, and alcohol withdrawal. Their mechanisms of action are incompletely understood, but are thought to involve inhibition of α₂δ subunit-containing voltage-gated calcium channels. Here, we report that gabapentin is a potent activator of the heteromeric KCNQ2/3 voltage-gated potassium channel, the primary molecular correlate of the neuronal M-current, and also homomeric KCNQ3 and KCNQ5 channels. In contrast, the structurally related gabapentinoid, pregabalin, does not activate KCNQ2/3, and at higher concentrations (≥10 µM) is inhibitory. Gabapentin activation of KCNQ2/3 (EC₅₀ = 4.2 nM) or homomeric KCNQ3* (EC₅₀ = 5.3 nM) channels requires KCNQ3-W265, a conserved tryptophan in KCNQ3 transmembrane segment 5. Homomeric KCNQ2 or KCNQ4 channels are insensitive to gabapentin, whereas KCNQ5 is highly sensitive (EC₅₀ = 1.9 nM). Given the potent effects and the known anticonvulsant, antinociceptive, and anxiolytic effects of M-channel activation, our findings suggest the possibility of an unexpected role for M-channel activation in the mechanism of action of gabapentin.

2017-01-01·Basic & Clinical Pharmacology & Toxicology3区 · 医学

The pan‐Kv7 (KCNQ) Channel Opener Retigabine Inhibits Striatal Excitability by Direct Action on Striatal Neurons In Vivo

3区 · 医学

Article

作者: Mikkelsen, Maria D. ; Rode, Frederik ; Hansen, Henrik H. ; Mikkelsen, Jens D. ; Weikop, Pia

AbstractCentral Kv7 (KCNQ) channels are voltage‐dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan‐Kv7 channel opener retigabine. The effect of retigabine likely involves the inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal retigabine administration on striatal neuronal excitability in the rat determined by c‐Fos immunoreactivity, a marker of neuronal activation. When retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c‐Fos‐positive neurons after a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo.