Atheris Laboratories, Bernex-Geneva, Switzerland.
Br J Pharmacol. 2012 Jul;166(5):1654-68. doi: 10.1111/j.1476-5381.2012.01837.x.
The µ-conopeptide family is defined by its ability to block voltage-gated sodium channels (VGSCs), a property that can be used for the development of myorelaxants and analgesics. We characterized the pharmacology of a new µ-conopeptide (µ-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant.
µ-CnIIIC was sequenced, synthesized and characterized by its direct block of elicited twitch tension in mouse skeletal muscle and action potentials in mouse sciatic and pike olfactory nerves. µ-CnIIIC was also studied on HEK-293 cells expressing various rodent VGSCs and also on voltage-gated potassium channels and nicotinic acetylcholine receptors (nAChRs) to assess cross-interactions. Nuclear magnetic resonance (NMR) experiments were carried out for structural data.
Synthetic µ-CnIIIC decreased twitch tension in mouse hemidiaphragms (IC(50) = 150 nM), and displayed a higher blocking effect in mouse extensor digitorum longus muscles (IC = 46 nM), compared with µ-SIIIA, µ-SmIIIA and µ-PIIIA. µ-CnIIIC blocked Na(V)1.4 (IC(50) = 1.3 nM) and Na(V)1.2 channels in a long-lasting manner. Cardiac Na(V)1.5 and DRG-specific Na(V)1.8 channels were not blocked at 1 µM. µ-CnIIIC also blocked the α3β2 nAChR subtype (IC(50) = 450 nM) and, to a lesser extent, on the α7 and α4β2 subtypes. Structure determination of µ-CnIIIC revealed some similarities to α-conotoxins acting on nAChRs.
µ-CnIIIC potently blocked VGSCs in skeletal muscle and nerve, and hence is applicable to myorelaxation. Its atypical pharmacological profile suggests some common structural features between VGSCs and nAChR channels.
µ-conopeptide 家族以其阻断电压门控钠离子通道（VGSCs）的能力为特征，这一特性可用于开发肌肉松弛剂和镇痛药。我们对一种新型 µ-conopeptide（µ-CnIIIC）在一系列制剂和分子靶标上的药理学进行了表征，以评估其作为肌肉松弛剂的潜力。
µ-CnIIIC 经过测序、合成，并通过其直接阻断小鼠骨骼肌诱发的抽搐张力和小鼠坐骨和派克嗅觉神经的动作电位来进行特征描述。µ-CnIIIC 还在表达各种啮齿动物 VGSCs 的 HEK-293 细胞上以及电压门控钾通道和烟碱型乙酰胆碱受体（nAChRs）上进行了研究，以评估交叉相互作用。还进行了核磁共振（NMR）实验以获取结构数据。
合成的 µ-CnIIIC 降低了小鼠膈肌的抽搐张力（IC50 = 150 nM），与 µ-SIIIA、µ-SmIIIA 和 µ-PIIIA 相比，在小鼠伸趾长肌中显示出更高的阻断效果（IC = 46 nM）。µ-CnIIIC 以持久的方式阻断 Na(V)1.4（IC50 = 1.3 nM）和 Na(V)1.2 通道。在 1 µM 时，心脏 Na(V)1.5 和 DRG 特异性 Na(V)1.8 通道未被阻断。µ-CnIIIC 还阻断了 α3β2 nAChR 亚型（IC50 = 450 nM），并且在较小程度上阻断了 α7 和 α4β2 亚型。µ-CnIIIC 的结构测定显示出与作用于 nAChR 的 α-conotoxin 一些相似之处。
µ-CnIIIC 强烈阻断骨骼肌和神经中的 VGSCs，因此适用于肌肉松弛。其非典型的药理学特征表明 VGSCs 和 nAChR 通道之间存在一些共同的结构特征。
