CN116440126B - 一种1h-吲哚-3-丙酰胺类钠通道调控剂的应用 - Google Patents
一种1h-吲哚-3-丙酰胺类钠通道调控剂的应用 Download PDFInfo
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Abstract
本发明提供一种1H‑吲哚‑3‑丙酰胺类钠通道调控剂的应用，本发明提供的1H‑吲哚‑3‑丙酰胺类化合物是结构新颖的钠通道调控剂，具有较高的活性，在细胞水平的电生理实验中，对电压门控钠离子通道1.7亚型(hNav1.7)受体起到显著的抑制效果，可作为电压门控钠离子通道1.7亚型(hNav1.7)受体的小分子调控剂，因此将其应用到与钠通道相关的疾病的治疗中具有潜在应用价值。所述1H‑吲哚‑3‑丙酰胺类钠通道调控剂的化合物结构通式如式I所示：
Description
技术领域
本发明属于制药领域，具体涉及一种1H-吲哚-3-丙酰胺类钠通道调控剂的应用。本发明的1H-吲哚-3-丙酰胺类衍生物是钠通道调控剂，可用于治疗钠通道相关疾病的药物。
背景技术
电压门控钠离子通道(Voltage-gated Sodium Channels，VGSCs/Navs)是一种异源跨膜蛋白，在真原核生物体内广泛存在，主要功能是控制钠离子进出细胞。从整体上讲，VGSC可以分为真核钠离子通道和原核钠离子通道两大类。真核钠离子通道由一个α亚基(约260kDa)和一个或多个β亚基(30～40kDa)组成，其中α亚基构成了钠离子通道的主体结构，β亚基主要起调节作用。目前为止，哺乳动物体内已经鉴定出10种α亚基结构，彼此之间具有高度同源性(序列同源性大于70％)，并依据α亚基的不同分为10种钠离子通道亚型(Nav1.1～Nav1.9和Nax)。Nax与Nav1.7同源相似性极高，但无法起到传导离子的作用，被认为与离子稳态有关，因此研究领域内普遍承认前9种亚型存在。此外，哺乳动物体内已经鉴定出5种β亚基(β1、β1B、β2、β3和β4)，它们在调节α亚基的表达和跨膜运输、通道激活和失活以及配体结合方面具有重要作用。2017年，颜宁课题组解析出了鳗鱼的Nav1.4与β1的冷冻电镜结构(EeNav1.4，PDB ID：5XSY)，首次揭示了α亚基和β亚基之间的相互作用。
从微观结构分析，真核钠离子通道的α亚基可以分为D1～DIV四个结构域，结构域之间通过loop区彼此相连，每个结构域包含6个α螺旋跨膜片段(S1～S6)。S1～S4组成电压感知域(Voltage Sensor Domains，VSD)，S5～S6以及胞外loop区组成离子选择性中心孔道(Pore Domain，PD)。VSD是VGSC中感知电压变化的主要功能区，其中S4含有4～8个均匀分布的正电残基(Arg/Lys)，是电压传感的“门控电荷簇”。PD是把控离子选择性出入的关键功能区，PD最窄的区域称为离子选择性过滤器(Selective Filter，SF)，是把控钠离子进入的“关卡”。SF主要由来自于DI～DIV的S5～S6的四个残基构成，在哺乳动物体内，决定VGSC离子选择性的关键残基组是Asp/Glu/Lys/Ala(D/E/K/A)。此外，在DII～DIII之间存在锚定蛋白域(Ankyrin-binding Domain)，被认为与VGSC的定位有关；DIII～DIV之间存在Ile-Phe-Met(I-F-M)高度保守的三联体结构，在VGSC的快速失活中发挥重要作用。
除了上述的经典结构以外，细菌VGSC结构解析发现，NavAb(PDB ID：3RVY)存在分布于膜内的侧向开口，称为“开窗”(Fenestrations)，与PD直接相连。后续研究表明，开窗结构在真原核VGSC中均存在。分子动力学模拟研究显示，开窗提供了疏水性结合孔道，与小分子阻滞剂的结合有关，可能存在变构调节机制。
由于VGSC结构复杂、分子量大，结构解析研究面临着巨大挑战。随着X-射线衍射和冷冻电镜等技术的发展，VGSC的结构解析取得了巨大进展，代表性结构解析成果如表1所示。
表1 VGSC结构解析进展汇总(部分)
VGSC在人体各组织器官中广泛分布表达，与多种生理活动密切相关。Nav1.1、Nav1.2、Nav1.3和Nav1.6主要在中枢神经系统(CNS)中表达，与癫痫、偏头痛、自闭症、共济失调等疾病相关；Nav1.4主要在骨骼肌中表达，与高/低钾性周期性麻痹、同型副肌张力障碍等疾病相关；Nav1.5主要在心肌中表达，是治疗心脏疾病的重要靶点，但同时也是其他亚型选择性药物开发时必须规避的亚型；Nav1.7在鼻腔、呼吸道、皮肤等多个部位广泛表达，与过敏性鼻炎、哮喘、皮炎等多种疾病密切相关；Nav1.8和Nav1.9通常在周围神经系统中表达，与慢性疼痛等疾病相关。从药物开发价值角度考虑，Nav1.7是目前药物研发的主要靶点，对于疾病治疗具有重要意义。
因此，开发高活性的钠通道调控剂是当下药物研发的热点，开发更多、结构更加新颖的高活性钠通道调控剂以扩展临床用药选择是本领域技术人员需要解决的问题。
发明内容
本发明的目的在于提供一种1H-吲哚-3-丙酰胺类钠通道调控剂的应用，所述应用是1H-吲哚-3-丙酰胺类钠通道调控剂制备治疗钠通道相关疾病的药物，所述钠通道相关疾病包括如神经性疼痛、阵发性瘙痒、过敏性鼻炎、神经性嗅觉障碍等，临床表现为疼痛、肌肉抽搐、哮喘等。
本发明提供的1H-吲哚-3-丙酰胺类钠通道调控剂的化合物结构通式如式I所示：
其中，R1选自取代或不取代羧基的含碳数为1～6的烷基、且Ar1为苯、吡啶、嘧啶中的一种，Ar2为吡咯、咪唑、1,2,3-三氮唑、1,2,4-三氮唑、四氮唑、呋喃、噁唑、噁二唑、异噁唑、噻吩、噻唑中的一种，R5、R6为氢、含碳数为1～4的烷基、烷氧基、含氟烷基、含氮烷基、卤素、氰基、羟基、/>中的一种。R7、R8为含碳数为1～3的烷基，相连时R7、R8和N组成四元环、五元环或六元环。
R2选自含碳数为1～4的烷基、且Ar3为苯、吡啶、嘧啶、吡嗪中的一种，R9为氢、含碳数为1～4的烷基、环烷基、含氟烷基、烷氧基、含氮烷基、卤素、氰基、羟基中的一种。
R3、R4选自含碳数1～7的烷基、环烷基、含氮烷基、烷氧基、其中n取自0～3，Y为CH或N，R10取自氢、卤素、羟基、甲氧基、三氟甲基、二氟甲基中的一种。R3、R4可以和N组成四元环、五元环或六元环。
根据式I所示，本发明所要求保护的化合物结构具体如下表2所示。
表2
所述1H-吲哚-3-丙酰胺类化合物包括其药学上可接受的盐、前药、立体异构体、氘代物以及溶剂合物中的任意一种。
本发明提供的1H-吲哚-3-丙酰胺类化合物是结构新颖的钠通道调控剂，具有较高的活性，在细胞水平的电生理实验中，对电压门控钠离子通道1.7亚型(hNav1.7)受体起到显著的抑制效果，可作为电压门控钠离子通道1.7亚型(hNav1.7)受体的小分子调控剂，因此将其应用到与钠通道相关的如神经性疼痛、阵发性瘙痒、过敏性鼻炎、神经性嗅觉障碍等疾病的治疗中，具有潜在应用价值。
附图说明
图1为化合物WN1对电压门控钠离子通道1.7亚型(hNav1.7)受体的抑制活性。
图2为化合物WN2对电压门控钠离子通道1.7亚型(hNav1.7)受体的抑制活性。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
一、基于结构的虚拟筛选(化合物WN1的获得)
实验原理：利用基于结构的虚拟筛选，对化合物数据库中的化合物与电压门控钠离子通道1.7亚型(hNav1.7)受体之间的结合模式和结合自由能进行预测，筛选能够和电压门控钠离子通道1.7亚型(hNav1.7)受体结合的小分子化合物。
实验方法：基于电压门控钠离子通道1.7亚型(hNav1.7)受体的晶体结构(PDB编号：6J8J)，采用Schrodinger分子模拟软件包的Glide分子对接模块对chemdiv和specs小分子数据库进行了基于结构的虚拟筛选，取打分最佳的5000个化合物进行构象分析，采用Schrodinger分子模拟软件包的Canvas模块进行化合物结构过滤，随后采用MOE软件包进行结构聚类，最后经过人工挑选，最终购买30个化合物，用于活性筛选，实验方法与(三)中相同。
实验结果：筛选得到1个潜在钠通道调控剂，即化合物WN1：
二、化合物计算结构改造(化合物WN2的获得)
实验原理：针对化合物WN1进行计算结构改造，目的是得到活性更加优异的潜在钠通道调控剂。
实验方法：基于化合物WN1的结构，采用MOE软件包计算分子指纹，对chemdiv数据库进行搜索，相似性阈值设置为85％，经过人工挑选，最终购买37个化合物，用于活性测试，实验方法与(三)中相同。
实验结果：筛选得到1个活性更加优异的潜在钠通道调控剂，即WN2：
三、针对电压门控钠离子通道1.7亚型(hNav1.7)受体的抑制率测试
实验原理：膜片钳技术是一种通过微电极与细胞膜之间形成紧密接触的方法，采用电压钳或电流钳技术对生物膜上离子通道的电活动进行记录的微电极技术。将电极接触细胞，轻轻地给予负压吸引，待形成高阻封接后，继续施加负压或电击的方法打破细胞膜，即形成全细胞记录模式。使用以下方法刺激：细胞膜电位钳制在-120mV，电流由从-120mV到+60mV，以5mV步阶维持50ms的去极化簇诱发。稳态失活通过使用标准双脉冲协议刺激，其中50ms去极化测试电位为-30mV，然后是500ms预脉冲，范围从-130mV到-35mV，以5mV步阶。
实验方法：
1、细胞转染：
(1)实验前细胞传代至35mm的细胞培养皿中，备用。
(2)培养细胞至密度达到80-90％之间，即可进行后续实验。弃细胞培养液，PBS润洗一次后，加入2mL无血清Opting-MEM。
(3)取两个已灭菌的1.5mL离心管，做好标记后加入250μl Opting-MEM备用。
(4)配置A液：取A管，加入10μl lipofectamine 2000，轻轻混匀后，室温下静置5min。(转染质粒的质量与转染试剂的体积之比为1:2)。
(5)配置溶液B：取B管，加入3μg Nav1.7、1μgβ1和1μgβ2亚基，混匀后，室温静置5min。(转染其他钠通道亚型时加入的质粒DNA的量为4μg，另需加入0.5μg eGFP用于指示阳性细胞)。
(6)将A液与B液充分混匀，室温下静置20min。
(7)20min后，将DNA-脂质体轻轻滴加入已换液的细胞中，细胞继续在37℃恒温细胞培养箱中培养。
(8)转染4-6小时后，进行分皿(分皿时需特别注意细胞密度的控制，细胞密度不宜过高)。
(9)培养细胞24h后，可用于后续实验。
2、电生理记录：
使用的数据采集放大器为EPC10 USB Amplifier(HEKA，德国)，数据记录和控制软件为PatchMaster(HEKA，德国)，微电极玻璃毛细管购自武汉微探科学仪器有限公司(产品号：B15013F，材质：硼硅酸盐玻璃3.3，长度80mm，外径1.5mm，内径1.14mm)，电极由PC-10电极拉制仪拉制而成。采用80％串联电阻补偿，使电压误差降至最低。在建立全细胞模式后，等待5min后，使用Patchmaster记录电压依赖性电流，在30kHz时采样，并以2.9kHz滤波。
实验前必须将细胞外液置于室温下平衡后再更换培养皿内的培养液，以防止溶液温度的剧烈变化。更换溶液时要防止细胞从培养皿底部脱落。倒置显微镜下选择细胞膜较为光滑、细胞质均匀的细胞，在室温20-25℃条件下进行膜片钳实验。选用1.5mm外径的硼硅酸盐玻璃毛细管为玻璃电极材料，玻璃电极在拉制仪(PC-10，Narishige)上经两步拉制而成，玻璃电极热抛光后电极尖端口径为1.5-3.0μm，拉制完成后在玻璃电极内灌细胞内液。玻璃电极初始电阻为2.5MΩ左右比较好。待电极与细胞膜之间形成高阻封接(GΩ)后，补电极快电容。然后将细胞钳制在-20mV，给予一短而有力的负压，将钳制在电极中的细胞膜迅速打破，再补偿细胞慢电容。形成全细胞记录模式后将细胞钳制为-120mV，细胞稳定4min后开始记录电流。串联电阻(Rs)在实验过程中始终保持在5-10MΩ的范围之内最好能维持不变。
3、配置小分子化合物母液
所有小分子化合物均使用DMSO溶解成10mM或100mM的母液，为避免反复冻融，将其分装后于-80℃保存备用。
4、小分子化合物的稀释
实验前于-80℃冰箱中取出目标小分子化合物，于冰上溶解后，用细胞外液将其稀释至所需浓度(10μM)，备用。使用前溶液需恢复至室温。
实验结果：得到本文所述化合物对电压门控钠离子通道1.7亚型(hNav1.7)受体的抑制率，结果如表3所示。
表3本发明所述化合物的结构与对电压门控钠离子通道1.7亚型(hNav1.7)受体的抑制率
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四、化合物WN1对电压门控钠离子通道1.7亚型(hNav1.7)受体的抑制活性
实验原理：为了检测化合物WN1的抑制效果，我们采用(三)中的实验方法，经过多次不同浓度的梯度实验，测定化合物WN1对电压门控钠离子通道1.7亚型(hNav1.7)受体的抑制活性。
实验步骤：与(三)中步骤相同。
实验结果：如图1所示，化合物WN1对电压门控钠离子通道1.7亚型(hNav1.7)受体起到抑制作用。
五、化合物WN2对电压门控钠离子通道1.7亚型(hNav1.7)受体的抑制活性
实验原理：为了检测化合物WN2的抑制效果，从而验证化合物WN2相比化合物WN1是否获得提升，我们采用(三)中的实验方法，经过多次不同浓度的梯度实验，测定化合物WN2对电压门控钠离子通道1.7亚型(hNav1.7)受体的抑制活性。
实验步骤：与(三)中步骤相同。
实验结果：如图2所示，化合物WN2对电压门控钠离子通道1.7亚型(hNav1.7)受体起到明显抑制作用，活性强于化合物WN1。
Claims (2)
1.一种1H-吲哚-3-丙酰胺类钠通道调控剂在制备治疗神经性疼痛药物中的应用，其特征在于，1H-吲哚-3-丙酰胺类钠通道调控剂能显著抑制电压门控钠离子通道1.7亚型受体，所述1H-吲哚-3-丙酰胺类钠通道调控剂的化合物结构为WN1或WN2 />所示 。
2.根据权利要求1所述的应用，其特征在于，所述1H-吲哚-3-丙酰胺类化合物包括其药学上可接受的盐。
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