CN114028570A - α7烟碱型胆碱受体激动剂在制备肽酰基精氨酸脱亚氨酶4抑制剂中的用途 - Google Patents
α7烟碱型胆碱受体激动剂在制备肽酰基精氨酸脱亚氨酶4抑制剂中的用途 Download PDFInfo
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- CN114028570A CN114028570A CN202111614719.0A CN202111614719A CN114028570A CN 114028570 A CN114028570 A CN 114028570A CN 202111614719 A CN202111614719 A CN 202111614719A CN 114028570 A CN114028570 A CN 114028570A
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Abstract
本发明公开了α7烟碱型胆碱受体激动剂在制备肽酰基精氨酸脱亚氨酶4抑制剂中的用途，本发明首次对α7nAChR激动剂与PAD4表达与活力进行了实验研究，结果证明α7nAChR激动剂抑制PAD4表达与活力。揭示了α7nAChR激动剂在制备治疗PAD4相关疾病药物中的良好应用前景。
Description
技术领域
本发明涉及一类化合物的用途，具体涉及α7烟碱型胆碱受体激动剂在制备肽酰基精氨酸脱亚氨酶4抑制剂中的用途。
背景技术
肽酰基精氨酸脱亚氨酶4(peptidylarginine deiminase 4，PAD4)是PAD家族成员之一，在巨噬细胞、粒细胞和单核细胞等细胞中均有分布，依赖钙离子作用于细胞核的组蛋白，将带正电荷的组蛋白精氨酸转化为电中性的瓜氨酸残基，进而减弱组蛋白与带负电荷的DNA相互作用，使染色质疏松、核膜破裂，释放出松散的染色质和颗粒蛋白，最终形成网状结构。PAD4是一种重要的蛋白翻译后修饰酶，与多种细胞活动与功能相关。
PAD4在乳腺癌、直肠腺癌、食管腺癌和卵巢癌等多种肿瘤中高表达，直接参与肿瘤细胞的增殖与转移。PAD4在心血管疾病(急性冠状动脉综合征、动脉粥样硬化、心肌梗死等)和自身免疫性疾病(类风湿性关节炎、系统性红斑狼疮和多发性硬化等)中亦发挥重要的作用。此外，PAD4可通过促进中性粒细胞外诱捕网(NETs)形成在多种疾病中发挥间接作用。
PAD4已成为疾病诊断与治疗的一个重要酶，以PAD4为靶酶发现和研制治疗类风湿性关节炎、心血管疾病和恶性肿瘤等疾病的药物是目前的研究热点之一。现有的PAD4选择性抑制剂数量较少，主要包括氟脒(F-amidine)或氯脒(Cl-amidine)及其类似物YW3-56、GSK199等。这些化合物处于临床前研究阶段，临床疗效有待验证。发现新型的PAD4抑制剂具有重要的意义和潜在的治疗价值。
α7烟碱型乙酰胆碱受体(α7AchR)是乙酰胆碱受体的一种亚型，在神经、免疫、炎症和肿瘤等多种细胞均有表达。现已发现，α7AchR激动剂具有抗炎、免疫抑制、抗动脉粥样硬化、神经保护、抗内毒素血症、抗关节疼痛、改善记忆损伤、减缓肺动脉高压等药理活性。
发明内容
发明目的：本发明的目的在于提供α7AchR激动剂在制备抑制PAD4药物中的应用。具体的说，本发明所述的α7AchR激动剂在制备治疗自身免疫性疾病药物、治疗心血管疾病药物、治疗恶性肿瘤药物中的应用。
技术方案：α7烟碱型胆碱受体激动剂在制备肽酰基精氨酸脱亚氨酶4抑制剂中的用途。
α7烟碱型胆碱受体激动剂添加药学上可接受的辅料制备成制剂。
所述制剂为滴鼻剂、滴眼剂、散剂、丸剂、胶囊剂、片剂、微囊剂、软胶囊剂、膜剂、栓剂、注射剂、膏剂、酊剂、冲剂，气雾剂。
α7烟碱型胆碱受体激动剂在抑制肽酰基精氨酸脱亚氨酶4活性和表达中的应用。
α7烟碱型胆碱受体激动剂在制备由肽酰基精氨酸脱亚氨酶4介导的关节炎药物中的应用。
所述α7烟碱型胆碱受体激动剂包括PNU-282987、AR-R17779、青藤碱等。
本发明实验研究发现，在体外培养的巨噬细胞，α7nAChR激动剂可明显抑制佛波酯或脂多糖诱导的PAD4表达，下调PAD4催化产物(瓜氨酸化组蛋白H3)在胞内的累积；α7nAChR激动剂能显著抑制PAD4的活性。在胶原诱导的关节炎模型小鼠(人类类风湿性关节炎动物模型)，PNU-282987、AR-R17779和青藤碱均可显著抑制关节炎小鼠滑膜组织中PAD4的表达。
有益效果：本发明与现有技术相比，具有如下优点：(1)本发明首次对α7nAChR激动剂与PAD4表达与活力进行了实验研究，结果证明α7nAChR激动剂抑制PAD4活力与表达。(2)揭示了α7nAChR激动剂在制备治疗PAD4相关疾病药物中的应用前景。
附图说明
图1是α7烟碱型乙酰胆碱受体激动剂对巨噬细胞PAD4表达的影响(平均值±标准误，n＝3)；
图2是α7nAChR激动剂对PAD4胞内催化产物积累的影响(平均值±标准误，n＝3)；
图3是α7nAChR激动剂对PAD4活性的影响(平均值±标准误，n＝3)；
图4是α7nAChR激动剂对关节炎模型小鼠滑膜组织PAD4表达的影响(平均值±标准误，n＝8)。
具体实施方式
PNU-282987是购自美国MedChemexpress生物科技公司(HY-12560A)，AR-R17779是购自美国MedChemexpress生物科技公司(HY-135483A)。
实施例1
α7烟碱型乙酰胆碱受体激动剂对巨噬细胞PAD4表达的抑制作用
将RAW264.7细胞以1×105/mL的密度接种于12孔板，将细胞置于37℃、5％CO2培养箱中培养1h，分别在细胞培养基中加入α7nAChR激动剂PNU-282987、AR-R17779(5，10，20μM)、青藤碱(SIN，0.25，0.5，1mM)。30min后向细胞培养基中加入佛波酯(phorbol-12-myristate-13-acetate，PMA)或脂多糖(LPS，1μg/mL)。4h后提取细胞总蛋白，Western blot法检测PAD4表达水平。实验结果见图1，PNU-282987(10，20μM)、AR-R17779(10，20μM)、青藤碱(0.5，1mM)使巨噬细胞PAD4表达水平均得到大幅抑制。
实验结果显示，α7nAChR激动剂显著下调巨噬细胞PAD4表达水平。
实施例2
α7nAChR激动剂对PAD4胞内催化产物积累的抑制作用
将RAW264.7细胞以1×105/mL的密度接种于12孔板，将细胞置于37℃、5％CO2培养箱中培养1h，在细胞培养基中加入α7nAChR激动剂PNU-282987、AR-R17779(5，10，20μM)、青藤碱(SIN，0.25，0.5，1mM)。30min后向培养基中加入PMA或LPS(1μg/mL)。4h后提取细胞总蛋白，Western blot法检测PAD4的胞内催化产物(瓜氨酸化组蛋白H3)积累水平。实验结果见图2，PNU-282987(10，20μM)、AR-R17779(10，20μM)、青藤碱(0.5，1mM)使巨噬细胞中组蛋白H3的瓜氨酸化水平明显降低。
试验结果显示，α7nAChR激动剂显著下调巨噬细胞中组蛋白H3的瓜氨酸化水平，显著抑制PAD4的胞内催化产物积累。
实施例3
α7nAChR激动剂对PAD4活性的抑制作用
将α7nAChR激动剂PNU-282987(0.25，0.5，1，2，4，8mM)、AR-R17779(0.25，0.5，1，2，4，8mM)、青藤碱(SIN，1，2，4，8，16，32mM)加入至含有100mM Tris(pH 7.2)、10mM氯化钙、10mM DL-二硫苏糖醇和0.2ml重组PAD4溶液的反应缓冲液，37℃孵育2min。加入含精氨酸的短肽、10mM N-α-苯甲酰精氨酸乙酯开始反应，然后将反应体系在37℃温育30min。加入60％(w/v)高氯酸终止酶促反应。将由六水硫酸亚铁铵和十二水硫酸铁铵在1N H2SO4中制备的氧化还原试剂加入反应混合物中，然后煮沸10min。冷却至室温后，加入酸混合物(磷酸、硫酸和去离子水)和12.5mM 2，3-丁二酮一肟溶液。煮沸20min后冷却，在490nm处测定吸光度并计算抑制率。实验结果见图3，PNU-282987(0.25，0.5，1，2，4，8mM)、AR-R17779(0.25，0.5，1，2，4，8mM)、青藤碱(1，2，4，8，16，32mM)抑制了PAD4活性。
实验结果显示，a7nAChR激动剂显著抑制PAD4的活性。
实施例4
α7nAChR激动剂对关节炎模型小鼠滑膜组织PAD4表达的抑制作用
采用DBA/1J小鼠构建胶原诱导的关节炎模型，初次免疫28天后根据疾病评分对模型小鼠重新分为模型组(Model)、AR-R17779组(5mg/kg，腹腔注射)、PNU-282987组(120mg/kg，灌胃给药)、青藤碱(120mg/kg，灌胃给药)。初次免疫后42天，放血处死小鼠，提取小鼠的踝关节滑膜组织，免疫荧光法检测PAD4表达水平。实验结果见图4，AR-R17779(5mg/kg，腹腔注射)、PNU-282987(120mg/kg，灌胃给药)和青藤碱(120mg/kg，灌胃给药)抑制了关节炎模型小鼠滑膜组织PAD4表达。
实验结果显示，α7nAChR激动剂显著抑制关节炎模型小鼠滑膜组织PAD4的表达。
实施例5
PNU-282987 100mg，与淀粉40mg、糊精60mg混合，用适量25％乙醇作湿润剂，制成软材，常规方法制粒，加入硬脂酸镁混合，制成片剂。
PNU-282987 50mg，与淀粉70mg、糊精10mg、糖粉10mg混合，用30％乙醇作润湿剂，制成软材，湿法制粒，然后装胶囊，制成胶囊剂。
AR-R17779 50mg，与淀粉40mg、滑石粉10mg混合采用常规技术制成散剂。
AR-R17779 100mg，与糖粉15mg、水8mL采用常规技术制成糖浆剂，再加入淀粉70mg采用常规技术制备成丸剂。
PNU-282987 50mg，与0.9％氯化钠溶液10mL、薄荷油10mL、甘油15mL采用常规技术混合均匀后分装，制成滴鼻剂。
PNU-282987 50mg，与海藻糖200mg(渗透压保护剂)、氯化钠60mg(渗透压调节剂)、碳酸氢钠4mg(pH调节剂)、玻璃酸钠10mg(粘稠剂)、羟苯乙酯3mg(抑菌剂)混合后溶于100mL注射用水，采用常规技术过滤、分装，制成滴眼剂。
PNU-282987 50mg，与乙基纤维素乙醇溶液(乙基纤维素80mg、乙醇6mL)混合均匀后经喷雾干燥法制成颗粒，将颗粒与无水乳糖100mg、微晶纤维素100mg、二氧化硅1mg、交联聚维酮60mg、硬脂酸镁1mg混合均匀，经常规技术制成片剂，得微囊化片剂，即为微囊剂。
AR-R17779 50mg，与1，2-丙二醇85g、无水乙醇25g、脱水山梨醇单油酸酯100g、中链三酰甘油100g、Cremophor RH40100g于50℃水浴中50r/min搅拌均匀混合，至形成黄色均一透明的液体，即得到AR-R17779自乳化微乳内容物；将内容物采用常规技术制成软胶囊剂。
AR-R17779 50mg，与羧甲基纤维素钠溶液(1∶10)92mL、丙二醇3g研磨混合均匀后采用常规技术制成膜剂。
AR-R17779 50mg，与融化后的PEG1000 356mg、PEG4000 356mg、甘油1.7mL混合均匀，采用常规技术制成栓剂。
AR-R17779 50mg，与苯甲醇10mL、氯化钠8g、注射用水加至100mL，采用常规技术制成注射剂。
AR-R17779 50mg，与羧甲基纤维素钠4mg、液体石蜡20mL、75％乙醇5mL于38g热融化的凡士林中搅拌均匀，冷却至室温后常规技术制成膏剂。
AR-R17779 50mg，于10mL双蒸水中溶解后与90mL 65％乙醇混合均匀，制成酊剂。
AR-R17779 50mg，与乳糖90g、硬脂酸镁1.5g混合均匀压大片，将此预压片在摇摆式颗粒机中破碎，整粒，过2～3号筛制成冲剂。
AR-R17779 50mg，与2.5g聚山梨酯80、乙二胺四乙酸二钠2g、柠檬酸13.7g、柠檬酸钠10.1g、纯水35mL，搅拌溶解后定量分装至喷雾装置中，常规技术制成气雾剂。
青藤碱50mg，与乙基纤维素乙醇溶液(乙基纤维素80mg、乙醇6mL)混合均匀后经喷雾干燥法制成颗粒，将颗粒与无水乳糖100mg、微晶纤维素100mg、二氧化硅1mg、交联聚维酮60mg、硬脂酸镁1mg混合均匀，经常规技术制成片剂，即为微囊化片剂。
青藤碱50mg，与1，2-丙二醇85g、无水乙醇25g、脱水山梨醇单油酸酯100g、中链三酰甘油100g、Cremophor RH40 100g于50℃水浴中50r/min搅拌均匀混合，至形成黄色均一透明的液体，即得到AR-R17779自乳化微乳内容物；将内容物采用常规技术制成软胶囊剂。
Claims (4)
1.α7烟碱型胆碱受体激动剂在制备肽酰基精氨酸脱亚氨酶4抑制剂中的用途。
2.根据权利要求1所述的用途，其特征在于，α7烟碱型胆碱受体激动剂添加药学上可接受的辅料制备成制剂。
3.根据权利要求2所述的用途，其特征在于，所述制剂为滴鼻剂、滴眼剂、散剂、丸剂、胶囊剂、片剂、微囊剂、软胶囊剂、膜剂、栓剂、注射剂、膏剂、酊剂、冲剂，气雾剂。
4.α7烟碱型胆碱受体激动剂在抑制肽酰基精氨酸脱亚氨酶4活性和表达中的应用。
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2021
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| CN102657651A (zh) * | 2002-12-06 | 2012-09-12 | 范因斯坦医学研究院 | 用α 7受体结合胆碱能激动剂抑制炎症 |
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