CN117323333A - 岩黄连碱化合物在制备β2-肾上腺素受体阻断剂中的应用 - Google Patents
岩黄连碱化合物在制备β2-肾上腺素受体阻断剂中的应用 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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Abstract
本申请涉及岩黄连碱化合物的新用途技术领域,具体公开了一种岩黄连碱化合物在制备β2‑肾上腺素受体阻断剂中的应用。本申请的岩黄连碱可阻断交感神经传递、抑制神经节兴奋,从而防止毛发脱落。同时压力状态下,施用该药物可以抑制交感神经分泌去甲肾上腺素,在源头上预防去甲肾上腺素对黑色素干细胞的刺激,从而预防白发生成。本申请的岩黄连碱适用于具有心理焦虑、工作压力大、作息不规律和/或焦虑引起的头发脱毛明显增加的症状人群。
Description
技术领域
本申请涉及岩黄连碱化合物的新用途技术领域,尤其是涉及一种岩黄连碱化合物在制备β2-肾上腺素受体阻断剂中的应用。
背景技术
岩黄连碱的天然中药来源为延胡索,延胡索是罂粟科植物延胡索的干燥块茎,其具有活血,行气,止痛的功效;用于胸胁、脘腹疼痛,胸痹心痛,经闭痛经,产后瘀阻,跌扑肿痛。
肾上腺素受体可分为α和β两类,其中α受体主要分布在皮肤、肾脏、胃肠道等的血管平滑肌上,与相应递质结合会导致血管收缩和瞳孔放大;β受体主要分布在骨骼肌、肝脏、心脏的血管平滑肌上,与相应递质结合导致心脏兴奋、血管和支气管扩张、代谢变化。其中β受体又可分为β1、β2、β3,β1受体主要分布于心脏,可增加心肌收缩性,自律性和传导功能。β2受体主要分于支气管平滑肌,血管平滑肌和心肌等,介导支气管平滑肌松弛,血管扩张等作用;β3受体主要分布于白色及棕色脂肪组织,调节能量代谢,也介导心脏负性肌力及血管平滑肌舒张作用。
当β受体与G蛋白结合,激活腺苷酸环化酶(AC)使三磷酸腺苷(ATP)转化为环磷酸腺苷(CAMP),导致细胞内CAMP水平增高,CAMP激活PKA,PKA,磷酸化多种蛋白质,包括L型Ca2+通道,促进Ca2+内流,使细胞内Ca2+浓度升高,导致肌肉收缩力增强,磷酸化的受磷蛋白则增加肌浆网Ca2+的摄取,增强肌肉的舒张功能。去甲肾上腺素(norepinephrine,NA)主要由肾上腺和交感神经释放,可作用于α受体和β受体。毛囊中的多种细胞表面主要存在表达的肾上腺素受体为β2受体。
毛囊膨突部位中存在着黑色素干细胞,在毛发生长期时有所保留分化成黑色素细胞后分泌黑色素,为毛发进行染色。剩余的黑色素干细胞会后续进行自我复制,使得其数量保持稳定,从而让毛发保持长时间黑色。交感神经直接连接毛囊的膨突部位,在压力状态下,小鼠体内会分泌皮质酮和去甲肾上腺素,其中交感神经释放的去甲肾上腺素可直接作用于膨突中的黑色素干细胞,引起黑色素干细胞无保留地快速增殖分化,造成黑色素干细胞的枯竭,从而引起不可逆转的白发。
毛囊中的毛干能够稳定存在于毛囊结构中,是因为毛干与内根鞘之前细胞的互相粘附作用。细胞间粘附是通过细胞粘附因子之间的相互作用实现的,上皮细胞中存在的主要细胞粘附因子是E-Cadherin,这是一种钙离子(Ca2+)依赖性细胞粘附分子家族,需要细胞外Ca2+进行粘合功能,当E-Cadherin与Ca2+进行接触结合后,它会从非活性柔性细胞到更刚性的构象,并且与周围的E-Cadherin结合,形成完整坚固的粘附网,将细胞粘附在一起。而当细胞间Ca2+缺失后,E-Cadherin活性消失,导致细胞粘性下降,组织分解。毛囊是皮肤的粘附器官,是由上皮细胞发育而来,因此也会受到E-Cadherin的影响。毛囊细胞主要表达β2-肾上腺素受体,NA作用于毛囊上的β2-肾上腺素受体,直接导致毛囊细胞间的Ca2+内流,引起毛干从毛囊中脱落。
因此可以看出,去甲肾上腺素NA作用于毛囊细胞的β2-肾上腺素受体会对毛囊正常生理功能产生严重影响,但目前能够阻断β2-肾上腺素受体的药物数量有限,且不方便被开发,因此开发相关天然产物具有重要意义。
发明内容
本申请的目的在于克服上述现有技术的不足之处而提供一种岩黄连碱化合物在制备β2-肾上腺素受体阻断剂中的应用。
为实现上述目的,本申请采取的技术方案为:
第一方面,本申请提供了岩黄连碱化合物在制备β2-肾上腺素受体阻断剂中的应用。
本申请首次开发出岩黄连碱化合物可以阻断β2-肾上腺素受体,进而影响头发的生长。
第二方面,本申请提供了岩黄连碱化合物作为β2-肾上腺素受体阻断剂在制备防治脱发或白发的药物中的应用。
经过验证,岩黄连碱作为β2-肾上腺素受体阻断剂,可阻断交感神经传递、抑制神经节兴奋,从而防止毛发脱落。同时压力状态下,施用该药物可以抑制交感神经分泌去甲肾上腺素,在源头上预防去甲肾上腺素对黑色素干细胞的刺激,从而预防白发生成。
作为本申请所述应用的优选实施方式,所述岩黄连碱化合物在防治脱发或白发的药物中质量浓度为0.001~0.1mg/L。
作为本申请所述应用的优选实施方式,所述药物的剂型包括片剂、胶囊剂、注射剂、乳霜、凝胶、贴片、喷雾剂、软膏剂、硬膏剂、洗剂、搽剂、糊剂及泥敷剂中至少一种。
作为本申请所述应用的优选实施方式,所述岩黄连碱化合物阻断交感神经传递,抑制神经节兴奋,防止毛发脱落。
作为本申请所述应用的优选实施方式,所述岩黄连碱化合物作为β2-肾上腺素受体阻断剂时,肾上腺素受体与岩黄连碱的对接参数为:对接后评分为-6.6542,对接后分子变化方差为2.0700,对接后释放能量为50.7655。
作为本申请所述应用的优选实施方式,所述药物还包括药学上使用的辅料。
作为本申请所述应用的优选实施方式,所述辅料包括选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
作为本申请所述应用的优选实施方式,所述辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素中的至少一种。
与现有技术相比,本申请具有以下有益效果:
本申请提供了一种岩黄连碱化合物在制备β2-肾上腺素受体阻断剂中的应用,更提供了岩黄连碱化合物作为β2-肾上腺素受体阻断剂在制备防治脱发或白发的药物中的应用,本申请的岩黄连碱可阻断交感神经传递、抑制神经节兴奋,从而防止毛发脱落。同时压力状态下,施用该药物可以抑制交感神经分泌去甲肾上腺素,在源头上预防去甲肾上腺素对黑色素干细胞的刺激,从而预防白发生成。本申请的岩黄连碱适用于具有心理焦虑、工作压力大、作息不规律和/或焦虑引起的头发脱毛明显增加的症状人群。
附图说明
图1为β2-肾上腺素受体与普萘洛尔进行对接的示意图;
图2为β2-肾上腺素受体与岩黄连碱进行对接的示意图。
具体实施方式
为更好的说明本申请的目的、技术方案和优点,下面将结合附图和具体实施例对本申请作进一步说明。
在以下实施例中,所使用的实验方法如无特殊说明,均为常规方法,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
本申请通过运用计算机辅助药物技术,使用Molecular Operating Environment,将TCMSP数据库中的大量天然化合物与β2-肾上腺素受体的3D结构进行对接,筛选得到综合参数较好的化合物,岩黄连碱与β2-肾上腺素受体的对接良好,证明其可以与β2-肾上腺素受体进行结合。
β2-肾上腺素受体的三维结构从rcsbpdb(rcsb.org,编号6PS5)下载,普萘洛尔和岩黄连碱的三维结构从ChemicalBook(www.chemicalbook.com)下载。
通过运用计算机辅助药物技术,使用Molecular Operating Environment,将普萘洛尔和岩黄连碱分别与β2-肾上腺素受体的3D结构进行对接,参考表1-2。
表1β2-肾上腺素受体与普萘洛尔的对接参数
S | Rmsd refine | E conf | |
propranolol | -6.5223 | 1.5712 | 9.4502 |
表1中的“S”为对接后评分,负值越大表明对接越紧密;“rmsd_refine”为对接后分子变化方差,值越小越好;E_conf为对接后释放能量,值越大越好。
图1为使用分子对接软件Molecular Operation Environment(MOE)将β2-肾上腺素受体与普萘洛尔进行对接的示意图,由图1和表1可知,普萘洛尔与β2-肾上腺素受体连接紧密,参数合适,普萘洛尔可以阻断β2-肾上腺素受体。
表2β2-肾上腺素受体与岩黄连碱的对接参数
表2中的“S”为对接后评分,负值越大表明对接越紧密;“rmsd_refine”为对接后分子变化方差,值越小越好;E_conf为对接后释放能量,值越大越好。
图2为使用分子对接软件Molecular Operation Environment(MOE)将β2-肾上腺素受体与岩黄连碱进行对接的示意图。由图2和表2可知,岩黄连碱与β2-肾上腺素受体连接紧密,对接参数合适且比普萘洛尔(传统β2-肾上腺素受体阻断剂)更好,表明岩黄连碱可以阻断β2-肾上腺素受体。
本申请公开了岩黄连碱作为β2-肾上腺素受体阻断剂的应用,本申请的岩黄连碱可阻断交感神经传递、抑制神经节兴奋,从而防止毛发脱落,同时压力状态下,施用该药物可以抑制交感神经分泌去甲肾上腺素,在源头上预防去甲肾上腺素对黑色素干细胞的刺激,从而预防白发生成。
本岩黄连碱适用于具有心理焦虑、工作压力大、作息不规律和/或焦虑引起的头发脱毛明显增加的症状人群。
最后所应当说明的是,以上实施例仅用以说明本申请的技术方案而非对本申请保护范围的限制,尽管参照较佳实施例对本申请作了详细说明,本领域的普通技术人员应当理解,可以对本申请的技术方案进行修改或者等同替换,而不脱离本申请技术方案的实质和范围。
Claims (9)
1.岩黄连碱化合物在制备β2-肾上腺素受体阻断剂中的应用。
2.岩黄连碱化合物作为β2-肾上腺素受体阻断剂在制备防治脱发或白发的药物中的应用。
3.如权利要求2所述的应用,其特征在于,所述岩黄连碱化合物在防治脱发或白发的药物中质量浓度为0.001~0.1mg/L。
4.如权利要求2所述的应用,其特征在于,所述药物的剂型包括片剂、胶囊剂、注射剂、乳霜、凝胶、贴片、喷雾剂、软膏剂、硬膏剂、洗剂、搽剂、糊剂及泥敷剂中至少一种。
5.如权利要求2所述的应用,其特征在于,所述岩黄连碱化合物阻断交感神经传递,抑制神经节兴奋,防止毛发脱落。
6.如权利要求2所述的应用,其特征在于,所述岩黄连碱化合物作为β2-肾上腺素受体阻断剂时,肾上腺素受体与岩黄连碱的对接参数为:对接后评分为-6.6542,对接后分子变化方差为2.0700,对接后释放能量为50.7655。
7.如权利要求2所述的应用,其特征在于,所述药物还包括药学上使用的辅料。
8.如权利要求7所述的应用,其特征在于,所述辅料包括选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
9.如权利要求8所述的应用,其特征在于,所述辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素中的至少一种。
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