CN105878229B - 甘松萍瑚烷型倍半萜化合物的用途 - Google Patents
甘松萍瑚烷型倍半萜化合物的用途 Download PDFInfo
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- CN105878229B CN105878229B CN201510037564.7A CN201510037564A CN105878229B CN 105878229 B CN105878229 B CN 105878229B CN 201510037564 A CN201510037564 A CN 201510037564A CN 105878229 B CN105878229 B CN 105878229B
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Abstract
本发明提供了甘松萍瑚烷型倍半萜化合物异甘松新酮或甘松香酮E的新用途，该甘松萍瑚烷型倍半萜化合物从败酱科甘松属植物甘松(Nardostachys chinensis Batal.)的根茎中分离纯化而得，具有5‑羟色胺转运体(SERT)增强活性，属于少见的SERT活性促进剂，可在制备用于治疗抑郁症、焦虑症、精神分裂症、强迫症、神经退行性疾病、药物成瘾性等神经精神疾病以及慢传输性便秘、肠道易激综合征、和功能性腹胀等消化系统功能紊乱疾病的药物方面进行应用，具有重要的药物开发价值。
Description
技术领域
本发明涉及化合物的新用途，尤其是甘松萍瑚烷型倍半萜化合物的新用途。
背景技术
5-羟色胺转运体(SERT)是一种对5-HT有高度亲和力的跨膜转运蛋白，约含630个氨基酸残基，其编码基因(SLC6A4)分别位于7号和11号染色体上，由跨度约为35kb的14个外显子组成。SERT蛋白包含12～13个跨膜区，N端及C端位于胞质中，靠近N端处有cAMP依赖性蛋白激酶结合位点，在第三与第四跨膜区之间有一位于细胞外的环状部分，是N-连接的糖基化位点。
SERT属于Na+/Cl-依赖型转运蛋白,在中枢神经系统主要位于5-HT能神经元，SERT从神经突触间隙中重新摄取5-HT进入突触前神经元，直接影响突触间隙5-HT浓度，改变突触后受体介导信号的量和作用持续时间。在消化系统SERT主要位于肠粘膜上皮细胞，重新摄取肠道黏膜层的嗜铬细胞释放的5-HT来调节胃肠功能。此外，SERT在血小板、胎盘组织、骨髓、肾、肺、心、肾上腺、肝、甲状旁腺、甲状腺、胰腺等亦有分布，提示SERT参与多种生理功能。
SERT是转运5-HT的重要分子，在中枢神经系统与情绪、食欲、睡眠、记忆、学习等许多生理心理功能相关，SERT及5-HT表达改变可引起焦虑、抑郁、强迫症、恐惧症，甚至精神分裂症，并与药物成瘾性密切相关；在胃肠道功能性疾病中SERT扮演了重要角色，5-HT信号系统异常可导致胃肠道动力及分泌功能异常、内脏高敏感性,与慢性便秘、肠易激综合征、腹泻及功能性消化不良等胃肠道功能性疾病密切相关。
SERT是临床药物研发的重要靶点。基于SERT靶点的经典抗抑郁药多属于选择性SERT抑制剂(SSRI)，如氟西汀(Fluoxetine)等；5-羟色胺再摄取促进剂(SSRE)则少有报道，至今已报道SSRE有噻奈普汀(tianeptine)，别名达体朗(stablon)，其化学结构属三环类抗抑郁药，临床主要用于抗抑郁和抗焦虑。实验研究发现噻奈普汀可促进5-HT再摄取，在神经结构可塑性方面，噻奈普汀对应激/皮质酮诱导的海马神经元树突萎缩具有预防作用，能够对抗应激诱发的海马前体细胞增殖、海马体积下降和N-乙酰天冬氨酸浓度下降，并防止杏仁核树突过度增生。在神经兴奋性方面，噻奈普汀能够克服应激阻断海马长时程增强作用，逆转应激对海马-前皮层突触的抑制作用等。在神经保护方面，噻奈普汀能够降低海马和颞叶皮层的细胞凋亡。在记忆功能方面，噻奈普汀对应激诱导空间记忆损害具有阻断作用，增加记忆保留，有助于注意力集中行为，拮抗酒精的有害作用等(McEwen BS,OlieJP.2005.Neurobiology of mood,anxiety,and emotions as revealed by studies of aunique antidepressant:tianeptine.Molecular Psychiatry 10,525–537)。此外，噻奈普汀能使中枢5-HT代谢物5-羟吲哚乙酸升高，推断可能由于突触前膜再摄取-5-HT增加后，神经内5-HT分解代谢相应增高有关；噻奈普汀可作用于下丘脑-垂体-肾上腺轴,使下丘脑皮质激素释放因子及垂体前叶肾上腺皮质激素浓度下降。
噻奈普汀对重度抑郁症有效，对抑郁症长期疗效优于氟西汀，且安全性高，不良反应少，适合于老年抑郁症，抗焦虑效果优于氟西汀(胡萌，李臻.2007.噻奈普汀药理研究和临床应用进展.广东医学28(7)：1192-1193.)噻奈普汀对人体的作用特点包括：对心境紊乱有一定作用，介于镇静性抗抑郁药和兴奋性抗抑郁药之间；对躯体不适，尤其是对于焦虑和心境紊乱有关的胃肠不适有明显作用；对酒精中毒病人在戒酒期间出现的人格和行为紊乱有一定作用；而且，噻奈普汀对下列方面无不良作用：睡眠和警觉；心血管系统；胆碱能系统(无抗胆碱能症状)；药物成瘾。以上研究提示了5-羟色胺再摄取促进剂(SSRE)在临床应用中的特点和优势。
甘松(Nardostachys chinensis Batal.)是败酱科甘松属植物，具有理气止痛，开郁醒脾；外用祛湿消肿的功效，甘松已经报道的生物活性包括(1)作用于神经系统，如抗抑郁、镇静和抗惊厥、抗帕金森和记忆恢复；(2)作用于心血管系统，如降血压、抗心律失常、抗心肌缺血、抗心血管损伤；(3)作用于呼吸系统，如增强耐缺氧能力；(4)抑菌；(5)抗肝损伤等。甘松的化学成分包括倍半萜、三萜、环烯醚萜、香豆素、酚酸、黄酮等，倍半萜是其主要成分，其中甘松新酮、马兜铃烯等研究报道较多，其它活性成分特别是少量或微量成分鲜有报道，生物活性及相关机制还有待进一步发现。
分离得到的甘松萍瑚烷型倍半萜化合物具有结构通式(I)：结构中7,8-位为三元氧环，9位为酮羰基，1(10)-位形成双键，11位连有季碳羟基，2位(即R1和R2)可被羰基、羟基或氢取代，包括异甘松新酮和甘松香酮E等。另外，此类母核上11-羟基可被取代基酰化、酚醚化、酰胺化成酯、酚醚或含氮化合物。
发明内容
本发明所要解决的技术问题在于提供甘松萍瑚烷型倍半萜化合物的新用途。
为解决上述技术问题，本发明的技术方案是：
甘松萍瑚烷型倍半萜化合物在制备用于促进5-羟色胺转运体(SERT)活性的药物方面的应用，所述甘松萍瑚烷型倍半萜化合物具有如下结构通式(I)，
其中，R1和R2为H(异甘松新酮)，或R1和R2为O(甘松香酮E)。
当R1＝R2＝H时，所述异甘松新酮(Isonardosinone)化合物的理化及波谱学性质为：淡黄色结晶，UV(MeOH)λmax:197nm、235nm、259nm、306nm、335nm；CD(MeOH,c＝2.0×10-3)λ(Δε):243(+4.71)nm；氢谱、碳谱核磁数据见具体实施方式部分表1。
当R1＝R2＝O时，所述甘松香酮E(Kanshone E)化合物的理化及波谱学性质为：白色粉末，UV(MeOH)λmax:197nm、248nm；CD(MeOH,c＝1.9×10-3)λ(Δε):250(+4.02)、219(+0.11)nm；氢谱、碳谱核磁数据见具体实施方式部分表1。
上述甘松萍瑚烷型倍半萜化合物的制备方法如下：
(1)甘松根茎20Kg用70％乙醇浸提3次，每次48小时，合并提取液，减压浓缩，得粗提物浸膏3Kg；然后用70％乙醇热提上述药渣3次，每次2小时，合并提取液，减压浓缩，得粗提物浸膏400g；合并两次粗提物得总浸膏3.4Kg；
(2)所得粗提物总浸膏，经水分散后，分别用等体积的石油醚、乙酸乙酯和正丁醇依次萃取，得到石油醚部位320g、乙酸乙酯部位1Kg、正丁醇部位600g、水层1.2Kg；
(3)将石油醚部位320g经硅胶柱色谱(拌样硅胶100-200目400g，柱硅胶200-300目3.3Kg，石油醚：乙酸乙酯＝100:0～100:50溶剂系统梯度洗脱)，得22个流份Fr.1～22；
(4)流份Fr.5(石油醚：乙酸乙酯＝100:2溶剂洗脱流份)，经反复硅胶柱层析，分离得到化合物异甘松新酮和甘松香酮E。
优选的，甘松萍瑚烷型倍半萜化合物在制备用于治疗神经精神疾病，包括抑郁症、焦虑症、精神分裂症、强迫症、神经退行性疾病和/或药物成瘾性等的药物方面进行应用。
优选的，甘松萍瑚烷型倍半萜化合物在制备用于治疗消化系统功能紊乱疾病，包括慢传输性便秘、肠道易激综合征和/或功能性腹胀的药物方面进行应用。
实现上述用途的药物组合物，包含治疗有效量的甘松萍瑚烷型倍半萜化合物以及任选的药学可接受的赋形剂。
上述药学可接受的赋形剂可以是药物制剂领域中任何常规的赋形剂，特定赋形剂的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态，用于特定给药模式的合适药物组合物的制备方法完全在药物领域技术人员的知识范围内。例如，可以作为药学可接受的赋形剂包括药学领域常规的稀释剂、载体、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体和润滑剂等，必要时，还可以在药物组合物中加入香味剂、防腐剂和甜味剂等。
上述药物组合物可以制成片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂、注射乳剂、注射用无菌粉针等多种形式。上述各种剂型的药物均可以按照药学领域的常规方法制备。
本发明的有益效果是：
本发明所述甘松萍瑚烷型倍半萜类化合物，从败酱科甘松属植物甘松(Nardostachys chinensis Batal.)的根茎中分离纯化而得，具有促进5-羟色胺转运体(SERT)活性，可作为治疗抑郁症、焦虑症、精神分裂症、强迫症、神经退行性疾病、药物成瘾性等神经系统疾病以及慢传输性便秘、肠道易激综合征、和功能性腹胀等消化系统功能紊乱疾病的治疗药物，具有重要的药物开发价值。
附图说明
图1是2种甘松萍瑚烷型倍半萜化合物，异甘松新酮和甘松香酮E对SERT活性的增强作用，其中，阳性对照药2.0μM Fluoxetine，**p<0.01，***P<0.001，图中，A为异甘松新酮，B为甘松香酮E；
图2是甘松萍瑚烷型倍半萜化合物异甘松新酮的1H-NMR、13C-NMR谱图；
图3是甘松萍瑚烷型倍半萜化合物甘松香酮E的1H-NMR、13C-NMR谱图；
图4是甘松萍瑚烷型倍半萜化合物异甘松新酮的CD及UV图；
图5是甘松萍瑚烷型倍半萜化合物甘松香酮E的CD及UV图。
具体实施方式
为了使本领域的技术人员更好的理解本发明的技术方案，下面结合具体实施方式对本发明所述技术方案作进一步的详细说明。
实验仪器与试剂：傅里叶变换核磁共振波谱仪(瑞士Bruker公司，AVIII型400MHz及600MHz)；显色剂：10％硫酸乙醇。
实施例1
活性成分异甘松新酮和甘松香酮E化合物的制备(提取分离流程)：
甘松药材饮片购自安徽济人药业有限公司(批号：110709，规格：1Kg/袋，产地：四川)，约20Kg。甘松根茎20Kg用70％乙醇浸提3次，每次48小时，合并提取液，减压浓缩，得粗提物浸膏3Kg；然后用70％乙醇热提上述药渣3次，每次2小时，合并提取液，减压浓缩，得粗提物浸膏400g；合并两次粗提物得总浸膏3.4Kg；所得粗提物总浸膏，经水分散后，依次用等体积的石油醚、乙酸乙酯、正丁醇进行萃取，得到石油醚部位320g、乙酸乙酯部位1Kg、正丁醇部位600g、水层1.2Kg；将石油醚部位320g经硅胶柱色谱(拌样硅胶100-200目400g，柱硅胶200-300目3.3Kg，石油醚：乙酸乙酯＝100:0～100:50溶剂系统梯度洗脱)，得22个流份Fr.1～22；流份Fr.5(石油醚：乙酸乙酯＝100:2溶剂洗脱流份)，经反复硅胶柱层析分离得到该异甘松新酮(约15.0mg)和甘松香酮E(约8.0mg)。
异甘松新酮(Isonardosinone)，经检测为淡黄色结晶，UV(MeOH)λmax:197nm、235nm、259nm、306nm、335nm；CD(MeOH,c＝2.0×10-3)λ(Δε):243(+4.71)nm(图4)；氢谱、碳谱(图2)核磁数据见表1。与文献{Anjana Bagchi,Yoshiteru Oshima,HiroshiHikno.Kanshones D and E,Sesquiterpenoids of Nardostachys Chinensis roots[J].Phytochemwtry,1988,27:3667-3669.}报道数据基本一致，确定为一已知化合物，结构式如下图所示。
甘松香酮E(Kanshone E)，经检测为白色粉末，UV(MeOH)λmax:197nm、248nm；CD(MeOH,c＝1.9×10-3)λ(Δε):250(+4.02)、219(+0.11)nm(图5)；氢谱、碳谱(图3)核磁数据见表1。与文献{Bagchi A,Oshima Y,Hikino H.Kanshones D and E,Sesquiterpenoids ofNardostachys Chinensis roots[J].Phytochemistry,1988,27:3667-3669.}报道数据基本一致，确定为一已知化合物，具有如下结构通式(I)，
其中，R1和R2为H(异甘松新酮)，或R1和R2为O(甘松香酮E)。
表1.异甘松新酮和甘松香酮E化合物的核磁数据(CDCl3,1H-NMR in 400MHz,13C-NMR in 100MHz)
实施例2
本发明所述化合物对5-羟色胺转运体(SERT)的影响
采用稳定转染的hSERT-HEK293细胞株，以4-(4-(dimethylamino)phenyl)-1-methylpyridinium(APP+)为荧光底物，在高内涵系统上检测化合物双甘松烯酮A对SERT活性的影响。
1)实验仪器与试剂
实验仪器：
高内涵Operetta系统和Columbus数据管理和分析系统(PerkinElmer),超净台，移液枪(1000μL,200μL,20μL,10μL,2.5μL，美国Eppendorf公司)
试剂和材料：
人胚肾细胞系HEK293(中国科学院典型培养物保藏委员会细胞库)，hSERT pcDNA3质粒(Addgene,plasmid 15483),MEM培养基(Gibco),APP+(Sigma)，Hoechst 33342(CellSignaling Technology)，96孔板(Costar 3605)
2)实验操作过程
首先建立并鉴定了稳定表达hSERT-HEK293细胞株{安磊,李静,金增亮等.人源5-羟色胺转运体稳定表达细胞系的建立及其功能探究[J].军事医学2011,35(9):681-684}。以APP+为荧光底物，基于高内涵系统检测SERT的功能{Fowler A,Seifert N,Acker V.etal.A nonradioactive high-throughput/high-content assay for measurement of thehuman serotonin reuptake transporter function in vitro[J].Journal ofBiomolecular Screening,2006,11(8):1027-1034}
具体步骤：
(1)精密称取实施例1所得异甘松新酮和甘松香酮E，用DMSO配制成20mM的母液，用无酚红MEM基础培基稀释药物至10.0μM，1.0μM，0.1μM。
(2)按1.0×104细胞/孔的密度接种稳定转染的hSERT-HEK293细胞至96孔板中，在37℃，5％CO2条件下培养24h。
(3)实验设立空白对照组，阳性对照2.0μM Fluoxetine组，两种测试药物分别设立10.0μM，1.0μM，0.1μM组。细胞弃去培养基，用PBS缓冲液洗2遍，按照80μL/孔体积加入各待测样品，每个浓度3个复孔，在37℃，5％CO2条件下避光孵育2-3h。
(4)孵育完成后，每孔加入20μL APP+，孵育10分钟。
(5)弃去孔内的液体，用PBS缓冲液洗2遍，每孔加入1.0μg/mL Hoechst50μL，避光孵育20min。
(6)弃去孔板内的液体，PBS洗2-3遍，采用高内涵系统检测细胞内的荧光强度
Hoechst 33342Excitation：360-400nm，Emission：410-480nm
APP+Excitation：460-490nm，Emission：505-550nm
3)数据分析：
采用Columbus数据管理和分析系统进行图像分析，根据Hoechst 33342荧光识别细胞核方式来确定细胞，根据胞内APP+荧光强度来确定SERT转运活性，计算相对荧光强度＝(药物组的胞内APP+荧光强度/对照组的胞内APP+荧光强度)进行ANOVA分析。
4)实验结果
如图1-A所示，结果显示异甘松新酮显著增强SERT转运活性，Dunnett's MultipleComparison post hoc Test证实3个测试剂量异甘松新酮与空白对照组比较均显著增强了SERT活性，10.0μM(p<0.001),1.0μM(p<0.001)，0.1μM(p<0.01),阳性对照组2.0μMFluoxetine与空白对照组相比显著抑制了SERT活性(p<0.001)。
如图1-B所示，结果显示甘松香酮E显著增强SERT转运活性，并呈量-效依赖关系,Dunnett's Multiple Comparison post hoc Test证实2个测试剂量甘松香酮E与空白对照组比较均显著增强了SERT活性，10.0μM(p<0.001),1.0μM(p<0.001)，阳性对照组2.0μMFluoxetine与空白对照组相比显著抑制了SERT活性(p<0.001)。
综上可知，所述5-羟色胺转运体(SERT)是一种对5-HT有高度亲和力的Na+/Cl-依赖型转跨膜转运蛋白，在中枢神经系统主要位于5-HT能神经元，通过从神经突触间隙中重新摄取5-HT进入突触前神经元，直接影响突触间隙5-HT浓度，改变突触后受体介导信号的量和作用持续时间，从而参与多种生理心理功能(如情绪、食欲、睡眠、记忆、学习等)；在消化系统SERT主要位于肠粘膜上皮细胞，重新摄取肠道黏膜层嗜铬细胞释放的5-HT来调节胃肠功能，此外，在胎盘组织、生殖道、骨髓、肾、肺、心、肾上腺、肝、甲状旁腺、甲状腺和胰腺等器官均有分布，提示SERT参与多种生理功能。
SERT是临床药物研发的重要靶点，至今报道的5-羟色胺再摄取促进剂(SSRE)有噻奈普汀(tianeptine)，临床主要用于抗抑郁和抗焦虑。噻奈普汀对人体的作用特点包括：对心境紊乱有一定作用，介于镇静性抗抑郁药和兴奋性抗抑郁药之间；对躯体不适，尤其是对于焦虑和心境紊乱有关的胃肠不适有明显作用；对酒精中毒病人在戒酒期间出现的人格和行为紊乱有一定作用；而且，噻奈普汀对下列方面无不良作用：睡眠和警觉；心血管系统；胆碱能系统(无抗胆碱能症状)；药物成瘾。噻奈普汀属于一种SSRE，其作用特点提示了5-羟色胺再摄取促进剂(SSRE)在临床应用中的特点和优势。
本发明通过对从甘松根茎中分离得到的异甘松新酮和甘松香酮E进行体外影响5-羟色胺转运体(SERT)活性的研究，发现2种均能够显著增强SERT转运活性，从而确证异甘松新酮和甘松香酮E为调节SERT失衡引起的相关生理心理疾病和消化系统功能紊乱疾病有效成分。因此，异甘松新酮和甘松香酮E可以用来制备治疗抑郁症和焦虑症等神经精神疾病和肠道易激综合征等胃肠道功能紊乱疾病的药物。
上述甘松萍瑚烷型倍半萜化合物的结构中7,8-位为三元氧环，9位为酮羰基，1(10)-位形成双键，11位连有季碳羟基，2位(即R1和R2)可被羰基、羟基或氢取代，包括异甘松新酮和甘松香酮E。另外，此类母核上11-羟基可被取代基酰化、酚醚化、酰胺化成酯、酚醚或含氮化合物。
实施例3
制备方法：按上述比例将异甘松新酮/甘松香酮E、乳糖和淀粉均匀混合，过200目筛，用水均匀润湿，把润湿后的混合物干燥再过筛，加入硬脂酸镁，然后将混合物压片，每片重250mg，活性成分含量为10mg。
实施例4
胶囊剂：异甘松新酮/甘松香酮E 20mg
半乳糖 188mg
硬脂酸镁 2mg
制备方法：按上述比例将异甘松新酮/甘松香酮E与半乳糖均匀混合，过200目筛，把得到的混合物，加入硬脂酸镁，装入2号胶囊，即得。
上述参照具体实施方式对该甘松萍瑚烷型倍半萜化合物的新用途进行的详细描述，是说明性的而不是限定性的，可按照所限定范围列举出若干个实施例，因此在不脱离本发明总体构思下的变化和修改，应属本发明的保护范围之内。
Claims (1)
1.一种甘松萍瑚烷型倍半萜化合物在制备促进5-羟色胺转运体活性的试剂方面的应用，其特征在于：所述甘松萍瑚烷型倍半萜化合物具有如下结构通式(I)，
其中，R1和R2为H，或R1和R2为0。
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