Mechanism of Action and Structure–Activity Relationship of α-Conotoxin Mr1.1 at the Human α9α10 Nicotinic Acetylcholine Receptor,Journal of Medicinal Chemistry

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Mechanism of Action and Structure–Activity Relationship of α-Conotoxin Mr1.1 at the Human α9α10 Nicotinic Acetylcholine Receptor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-09-22 , DOI: 10.1021/acs.jmedchem.2c00494
Jiazhen Liang _{1,

2} , Han-Shen Tae ₃ , Zitong Zhao _{1,

2} , Xiao Li _{1,

2} , Jinghui Zhang _{1,

2} , Shen Chen _{1,

2} , Tao Jiang _{1,

2,

4} , David J Adams ₃ , Rilei Yu _{1,

2,

4}

Affiliation

α-Conotoxins (α-CTxs) can selectively target nicotinic acetylcholine receptors (nAChRs) and are important drug leads for the treatment of cancer, chronic pain, and neuralgia. Here, we chemically synthesized a formerly defined rat α7 nAChR targeting α-CTx Mr1.1 and evaluated its activity at human nAChRs. Mr1.1 was most potent at the human (h) α9α10 nAChR with a half-maximal inhibitory concentration (IC₅₀) of 92.0 nM. Molecular dynamic simulations suggested that Mr1.1 favorably binds at the α10(+)α9(−) and α9(+)α9(−) sites via hydrogen bonds and salt bridges, stabilizing the channel in a closed conformation. Although Mr1.1 and another antagonist, α-CTx Vc1.1 share high sequence similarity and disulfide-bond framework, Mr1.1 has distinct orientations at hα9α10. Based on the Mr1.1-hα9α10 model, analogues were generated, and the more potent Mr1.1[S4Dap], antagonized hα9α10 with an IC₅₀ of 4.0 nM. Furthermore, Mr1.1[S4Dap] displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.

中文翻译：

α-芋螺毒素 Mr1.1 对人 α9α10 烟碱乙酰胆碱受体的作用机制和构效关系

α-芋螺毒素 (α-CTxs) 可以选择性地靶向烟碱型乙酰胆碱受体 (nAChRs)，是治疗癌症、慢性疼痛和神经痛的重要药物先导物。在这里，我们化学合成了以前定义的大鼠 α7 nAChR，靶向 α-CTx Mr1.1，并评估了它对人类 nAChR 的活性。Mr1.1 对人 (h) α9α10 nAChR 最有效，半数最大抑制浓度 (IC ₅₀) 92.0 纳米。分子动力学模拟表明，Mr1.1 通过氢键和盐桥有利地结合在 α10(+)α9(−) 和 α9(+)α9(−) 位点，将通道稳定在封闭构象中。尽管 Mr1.1 和另一个拮抗剂 α-CTx Vc1.1 具有高度序列相似性和二硫键框架，但 Mr1.1 在 hα9α10 具有不同的方向。基于 Mr1.1-hα9α10 模型，生成了类似物，更有效的 Mr1.1[S4Dap] 以4.0 nM的 IC _{50拮抗 hα9α10。}此外，Mr1.1[S4Dap] 在大鼠慢性压迫性损伤 (CCI) 疼痛模型中显示出镇痛活性，因此是一种很有前途的候选药物。

更新日期：2022-09-22

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