A novel selective and orally bioavailable Nav1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability
A novel selective and orally bioavailable Nav1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability
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DOI：
10.1111/bph.13092
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发表时间：
2015-05-01
影响因子：
7.3
通讯作者：
Stevens, Edward B.
中科院分区：
文献类型：
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作者：
Payne, Claire Elizabeth;Brown, Adam R.;Stevens, Edward B.
背景和目的Na（V）1.8通道是设计治疗慢性疼痛的低分子量阻滞剂的重要分子靶点。在此，我们描述了PF-01247324（新一代选择性，新型化学型的口服生物可利用Na（v）1.8通道阻滞剂。实验方法使用体外贴片研究PF-01247324对Na（v）1.8通道的抑制作用。钳夹电生理学和口服生物利用度和抗伤害性效应使用体内啮齿动物模型的炎症和神经性疼痛证明。结果PF-01247324可抑制人背根神经节（DRG）神经元的河豚毒素抗性（TTX-R）电流（IC 50：331 nM）和重组表达的h Na（v）1.8通道（IC 50：196 nM），选择性是重组表达TTX-R hNa（v）1.5通道的50倍（IC 50：约10 M）和65-100倍的选择性超过TTX敏感（TTX-S）通道（IC 50：约10- 18 M）。小直径啮齿动物DRG神经元中的天然TTX-R电流被抑制，IC 50为448 nM，并且人重组Na（v）1.8通道和大鼠DRG神经元的TTX-R的阻断均具有频率和状态依赖性。体外电流钳显示，PF-01247324降低了大鼠和人DRG神经元的兴奋性，并改变了动作电位的波形。在啮齿动物体内实验表明，在炎症和神经性疼痛models.Conclusions和ImplicationsUsing PF-01247324的疗效，我们已经证实了Na（v）1.8通道在炎症和神经性疼痛的作用。我们还证明了Na（v）1.8通道在大鼠和人类DRG神经元的动作电位上冲和重复放电中的关键作用。
Background and PurposeNa(V)1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Na(v)1.8 channel blocker of novel chemotype.Experimental ApproachThe inhibition of Na(v)1.8 channels by PF-01247324 was studied using in vitro patch-clamp electrophysiology and the oral bioavailability and antinociceptive effects demonstrated using in vivo rodent models of inflammatory and neuropathic pain.Key ResultsPF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50: 331nM) and in recombinantly expressed h Na(v)1.8 channels (IC50: 196nM), with 50-fold selectivity over recombinantly expressed TTX-R hNa(v)1.5 channels (IC50: approximate to 10M) and 65-100-fold selectivity over TTX-sensitive (TTX-S) channels (IC50: approximate to 10-18M). Native TTX-R currents in small-diameter rodent DRG neurons were inhibited with an IC50 448nM, and the block of both human recombinant Na(v)1.8 channels and TTX-R from rat DRG neurons was both frequency and state dependent. In vitro current clamp showed that PF-01247324 reduced excitability in both rat and human DRG neurons and also altered the waveform of the action potential. In vivo experiments n rodents demonstrated efficacy in both inflammatory and neuropathic pain models.Conclusions and ImplicationsUsing PF-01247324, we have confirmed a role for Na(v)1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Na(v)1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons.