CN109674777A - 异绿原酸类化合物在制备神经退行性疾病和忧郁症的药物中的应用 - Google Patents
异绿原酸类化合物在制备神经退行性疾病和忧郁症的药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种异绿原酸类化合物在制备神经退行性疾病和忧郁症的药物中的应用,属于医药领域。发明人研究发现,异绿原酸类化合物(例如3,5‑二咖啡酰奎尼酸、3,4‑二咖啡酰奎尼酸等)对单胺氧化酶B具有很好的抑制活性,使其有望于开发成药物,参与由单胺氧化酶B异常所导致的疾病治疗中去,例如神经退行性疾病、忧郁症等。同时,由于传统中药金银花中富含异绿原酸类化合物,因此这一发现也拓展了对金银花药理活性的认知,有助于扩大金银花的开发与利用。
Description
技术领域
本发明涉及医药领域,具体而言,涉及一种异绿原酸类化合物在制备神经退行性疾病和忧郁症的药物中的应用。
背景技术
神经退行性疾病(Neurodegenerative disease)是一种大脑和脊髓的细胞神经元逐渐退化(死亡)的慢性疾病。大脑和脊髓的细胞一般不会再生,所以过度的损害可能是毁灭性的、不可逆转的。神经退行性疾病是由神经元或其髓鞘的丧失所致,随着时间的推移而恶化,以导致功能障碍。其主要包括帕金森症(Parkinson's disease,PD)、阿兹海默症(Alzheimer's disease,AD)等。
其中,帕金森症是第二高发的神经退行性疾病,在世界范围内有五百万至一千万的患病人群,引起病人运动障碍,严重危害患者的活动能力。其主要病理学特征是中脑基底神经节黑质致密部中的多巴胺能神经元死亡,黑质纹状体通路退化。目前临床药物对PD均采用对症治疗,新药的研发均是基于PD发病机制相关的关键靶点或信号通路而开展。脑内单胺氧化酶-B(MAO-B)是多巴胺分解代谢的关键酶之一,是抗PD药物研发的热门靶点。
目前,尚无对包括PD在内的神经退行性疾病有较好治疗效果的药物。鉴于此,特提出本申请。
发明内容
本发明的第一目的在于提供异绿原酸类化合物的新用途,开发其在治疗神经退行性疾病或忧郁症中的药用潜力。
本发明的第二目的在于提供一种用于治疗神经退行性疾病或忧郁症的药物组合物。
为了实现本发明的上述目的,特采用以下技术方案:
第一方面,本发明涉及异绿原酸类化合物在制备治疗或预防神经退行性疾病的药物中的应用。
进一步地,上述神经退行性疾病为帕金森症、阿尔茨海默病。
进一步地,异绿原酸类化合物包括3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸中的至少一种。
第二方面,本发明涉及金银花中异绿原酸类化合物在制备单胺氧化酶的抑制剂中的应用。
进一步地,上述单胺氧化酶为单胺氧化酶B。
进一步地,上述异绿原酸类化合物包括3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸中的至少一种。
第三方面,本发明涉及金银花中异绿原酸类化合物在制备治疗或预防忧郁症的药物中的应用,其中,上述异绿原酸类化合物包括3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸中的至少一种。
第四方面,本发明涉及一种用于治疗神经退行性疾病或忧郁症的药物组合物,其包括3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸中的至少一种,以及至少一种药学上可接受的辅料。
与现有技术相比,本发明的有益效果为:
本发明提供了一种异绿原酸类化合物的新用途以及包括其在内的组合物。发明人研究发现,异绿原酸类化合物(例如3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸等)对单胺氧化酶B具有很好的抑制活性,使其有望于开发成药物,参与由单胺氧化酶B介导的疾病治疗中去,例如神经退行性疾病、忧郁症等。同时,由于传统中药金银花中富含异绿原酸类化合物,因此这一发现也拓展了对金银花药理活性的认知,有助于扩大金银花的开发与利用。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限制本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
本实施方式提供一种异绿原酸类化合物的新用途。
金银花(Lonicera japonica)为我国传统的药食两用中药,具有清热解毒、疏散风热等功能,用于治疗痈肿疔疮、喉痹、丹毒、热毒血痢、风热感冒以及温病发热等症。现代药理研究表明其具有抗病原微生物、抗病毒、抗炎等作用。金银花的化学成分较为复杂,经研究表明,其含有较为丰富的异绿原酸类化合物,例如3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸。
发明人研究表明,异绿原酸类化合物对单胺氧化酶B具有较好的抑制活性,以3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸、1,3-二咖啡酰奎尼酸的效果最为突出。
其中,3,5-二咖啡酰奎尼酸,又称异绿原酸A,其分子式为C25H24O12,结构式为:
3,4-二咖啡酰奎尼酸,又称异绿原酸B,其分子式为C25H24O12,结构式为:
4,5-二咖啡酰奎尼酸,又称异绿原酸C,其分子式为C25H24O12,结构式如下:
1,3-二咖啡酰奎尼酸,又叫莱蓟素,其分子式为C25H24O12,结构式如下:
单胺氧化酶B(MAO-B)是一种定位在线粒体外膜的黄素蛋白酶,其功能是催化单胺类化合物的氧化脱氨,同时产生过氧化氢。主要分布在5-羟色胺能神经元、组胺能神经元和神经胶质细胞中。通过抑制MAO-B的活性可提高脑内多巴胺浓度,降低神经毒素水平,从而延缓黑质细胞的死亡过程。发明人研究发现,异绿原酸A、异绿原酸B和异绿原酸C对单胺氧化酶B较强的抑制活性,提示其可以开发成单胺氧化酶B抑制剂,或者开发成用于治疗由单胺氧化酶B介导的疾病,例如帕金森症、阿尔茨海默病等。
下面以帕金森症为例进行说明:
在帕金森症患者的脑中,黑质中多巴胺能神经元的减少导致MAO-B水平的上升。MAO-B氧化过量的多巴胺(Dopamine,DA)而产生过量的氧基团(如H2O2),这些氧基团会氧化破坏黑纹神经元;MAO-B还可以通过生物激活内源或外源的神经毒素来加速大脑的老化。
目前,MAO-B的抑制剂可以延缓病情的发展,已被广泛地用于PD的治疗中。司来吉兰是第一代不可逆的MAO-B选择性抑制剂,但其选择性较差,不良反应较大,会产生恶心、幻觉和高血压等危象。雷沙吉兰是第二代不可逆的MAO-B选择性抑制剂,但存在晕厥、直立性低血压、跌倒、头晕、头痛、背痛、关节痛、肌肉痛、感染、嗜睡、恶心、疲劳等不良反应。沙芬酰胺是新一代的MAO-B抑制剂,但其也存在运动障碍的不良反应。
由于现阶段的MAO-B抑制剂都存在一定的不良反应,因此,发明人对大量传统中药材进行筛选,从金银花中发现了具有MAO-B抑制活性的天然化合物——3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸,有望于将其二者应用于PD的治疗中,对于PD的预防及治疗具有重要意义。
此外,有研究表明,抑郁症患者中MAO-B表达量过高。且,临床上具有躁狂-抑郁表现的患者,其血小板中的MAO-B活性明显升高,经药物治疗后MAO-B活性显著下降。由此说明,MAO-B涉及抑郁症的临床症状。因此,本领域技术人员有理由认为MAO-B抑制剂能够改善抑郁症,对于抗抑郁症药物的研发具有一定的指导意义。
以下结合实验例对本发明的特征和性能作进一步的详细描述:
实验例
异绿原酸类化合物对MAO-B的体外抑制活性:
1.实验原理:
MAO-B在适宜反应条件下催化底物犬尿胺生成4-羟基喹啉,4-羟基喹啉在310nm的激发光下,产生400nm的发射光。通过检测310/400nm的荧光强度的变化来检测产物的生成量的变化,进而计算出抑制剂对MAO-B的抑制作用。
2.实验材料:
受试品:金银花提取物、3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸、1,3-二咖啡酰奎尼酸;
阳性对照:沙芬酰胺;
酶来源:购买商品化的MAO-B,-20℃保存。临用前12.5mM磷酸缓冲溶液(pH 7.4)将其稀释到工作液浓度(9U/mL)。
受试品及阳性对照处理:溶于含10%二甲基亚砜的12.5mM磷酸缓冲溶液(pH 7.4)中,浓度为0.1mg/mL。使用前稀释为所需浓度。
底物处理:将犬尿胺溶于12.5mM磷酸缓冲溶液(pH 7.4)中,浓度为0.2mM。
3.金银花提取物的制备:
取1g金银花粉末,用30mL 80%的甲醇超声提取30min,过滤,使用旋转蒸发仪浓缩滤液后得金银花提取物。
4.实验方法:
荧光分光光度法测定MAO-B活性:
本试验采用Corning白色不透明96孔酶标板,反应体系为200μL,温度为37℃。
药物反应组:取50μL酶和100μL受试品于96孔酶标板,37℃孵育10min,加入50μL犬尿胺,37℃孵育30min,加入80μL NaOH(2N)终止反应,激发/发射波长为310/400nm条件下读荧光强度,记为F1。
药物对照组:以50μL磷酸缓冲液代替药物反应组中的底物溶液,记荧光强度为F2。
空白反应组:以100μL磷酸缓冲液代替药物反应组中的受试品溶液,记荧光强度为F3。
空白对照组:以150μL磷酸缓冲液代替药物反应组中的底物溶液和受试品溶液,记荧光强度为F4。
按下式计算抑制率:
抑制率(%)=[1-(F1-F2)/(F3-F4)×100%]
5.实验结果及结论:
测定结果表1所示:
表1.金银花中组分对MAO-B的抑制活性
由表1可知,在体外酶活实验中,3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸均对MAO-B表现出较强的抑制活性,其在0.05mg/mL的浓度下,对MAO-B抑制率分别为78.14%、77.34%、77.31%和77.23%,远大于金银花提取物对MAO-B的抑制率(11.86%)。虽然3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸对MAO-B的抑制活性稍弱于阳性对照药物沙芬酰胺,但仍有很大的潜力作为候选药物,开发成为新一代的MAO-B抑制剂,用于神经退行性疾病或忧郁症的治疗或预防中。
尽管已用具体实施例来说明和描述了本发明,然而应意识到,在不背离本发明的精神和范围的情况下可以作出许多其它的更改和修改。因此,这意味着在所附权利要求中包括属于本发明范围内的所有这些变化和修改。
Claims (8)
1.异绿原酸类化合物在制备治疗或预防神经退行性疾病的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述神经退行性疾病为帕金森症、阿尔茨海默病。
3.根据权利要求1所述的应用,其特征在于,所述异绿原酸类化合物包括3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸中的至少一种。
4.异绿原酸类化合物在制备单胺氧化酶的抑制剂中的应用。
5.根据权利要求1所述的应用,其特征在于,所述单胺氧化酶为单胺氧化酶B。
6.根据权利要求1所述的应用,其特征在于,所述异绿原酸类化合物包括3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸中的至少一种。
7.异绿原酸类化合物在制备治疗或预防忧郁症的药物中的应用,其特征在于,所述异绿原酸类化合物包括3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸中的至少一种。
8.一种用于治疗神经退行性疾病或忧郁症的药物组合物,其特征在于,其包括3,5-二咖啡酰奎尼酸、3,4-二咖啡酰奎尼酸、4,5-二咖啡酰奎尼酸和1,3-二咖啡酰奎尼酸中的至少一种,以及至少一种药学上可接受的辅料。
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