CN1136847C - 异柳珊瑚酸在制药中的应用 - Google Patents
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Abstract
本发明涉及异柳珊瑚酸在制药领域中的新应用。该物质对人红细胞的乙酰胆碱酯酶具有显著选择性的抑制作用、对人血清BuChE无显著抑制作用，是一个可逆性乙酰胆碱酯酶抑制剂。它能提高脑神经中的乙酰胆碱酯水平，恢复乙酰胆碱酯神经传导，改善病人的记忆、认知和行为能力，延缓病情的发展，而且毒副作用小，可作为乙酰胆碱酯酶抑制剂应用，尤其可作为在制备治疗阿尔茨海默病的药中应用。
Description
本发明涉及倍半萜化合物异柳珊瑚酸(Isosubcrgorgic Acid)的用途，尤其涉及在制药领域中的用途。
随着世界人口平均寿命的提高，年龄相关性记忆缺损(AMMI)和阿尔茨海默病(Alzheimer’s Disease，简称AD)发病率上升，对其治疗药物的需求也日益增加；尤其是AD，一种临床上常见的神经退行性疾病(Neurodegenerative Disease)，它以记忆、认知及神经功能的受损为主要特征，病情的发展可引起严重的痴呆甚至死亡。在西方65岁以上人群中，约有5％的人患此病，我国60岁以上人群患此病率达到3.46％-3.9％，这给患者、家庭、社会造成严重的负担(据统计美国约有AD患者400万人，每年照顾病人费用高达900亿美元)：因此AD已经成为当前老年医学、神经科学、药物化学中极为关注的研究课题。
根据AD病因“胆碱能假说”，目前临床应用及处于临床研究中的抗AD药物主要是为了提高脑神经中的乙酰胆碱(ACh)含量水平，恢复ACh神经传导，改善病人的记忆、认知和行为能力，延缓病情的发展。其中一类药物是拟胆碱药(Cholinomimetic drugs)，由于拟胆碱药(乙酰胆碱酯酶抑制剂)有了明确的理论基础，因此它是现有条件下药物治疗AD的主要手段。乙酰胆碱酯酶抑制剂是AD治疗过程中使用最多、历史最久的一类药物。目前已发展到第二代乙酰胆碱酮酶抑制剂。倍半萜化合物异柳珊瑚酸(3-羧基-4.5.9-三甲基-11-羰基三环[6.3.0.01.5]十一-2-烯)，其结构式为[1]：分子式为C15H20O3，无色针状结晶，分子量为248，易溶于乙酸乙酯、三氯甲烷等有机溶剂。该化合物可由海洋生物侧扁软柳珊瑚(SubergogiaSuberosa)，通过物理和化学的方法，用几种途径得无色针状结晶物。已知该化合物可以用作乙酰胆碱醐酶复活剂。
本发明的目的在于提供倍半萜化合物异柳珊瑚酸的新用途，即在制药中的新应用。
本发明涉及倍半萜化合物异柳珊瑚酸作为乙酰胆碱酯酶抑制剂的应用，具体涉及异柳珊瑚酸作为制备治疗阿尔茨海默病的药中的应用。
为了更好地理解本发明的实质，下将用异柳珊瑚酸的药理、药效的试验结果来说明其在制药领域中的新用途。
异柳珊瑚酸----Isosubergorgic Acid是作为乙酰胆碱酪酶抑制剂(拟胆碱药)应用，可提高脑神经中的ACh水平，恢复ACh神经传导，改善病人的记忆、认知和行为能力，延缓病情的发展，尤其可用于阿尔茨海默病的治疗；目前国内外的拟胆碱药(乙酰胆碱酯酶抑制剂)：如他克林(Tacrine)、加兰他敏(Galanthamine)、Aricept(donepezil,E2020)、石杉碱甲(Huperzine A)等等都是含氮化合物。本发明的化合物分子中无氮元素，是一种新型拟胆碱药(乙酰胆碱酯酶抑制剂)；第二：异柳珊瑚酸对人红细胞的乙酰胆碱酯酶(AChE)有显著选择性的抑制作用(表二、五)，从而能提高脑神经中的ACh水平，恢复ACh神经传导，改善病人的记忆、认知和行为能力，延缓病情的发展；异柳珊瑚酸对人血清丁酰胆碱酯酶(BuChE)无显著抑制作用(表四)，而且是一个可逆性乙酰胆碱酯酶抑制剂(表三)；因此它不会象他克林(tacrine)，由于抑制假性胆碱酯酶(BuChE)而有副反应；第三：小鼠Y型迷宫实验中，异柳珊瑚酸的记忆成绩高于石杉碱甲(表一)，说明异柳珊瑚酸的疗效要稍高于临床药物石杉碱甲；第四：异柳珊瑚酸的LD50为68mg/Kg低于庚基毒扁豆碱(eptastigmine LD50为35mg/Kg)，更低于石杉碱甲(huperzne A)；第五：异柳珊瑚酸分子呈球状，在水和有机溶剂中都有一定的溶解度，因此可能通过血脑屏障，具有较好的选择性及中枢作用。
可将异柳珊瑚酸溶于吐温-80，或pH7.2磷酸盐缓冲液(2/15mol/L磷酸氢二钠溶液72ml与2/15mol/L磷酸二氢钾溶液28ml混合)，供动物体内外实验用。
实施例1
异柳珊瑚酸(Isosubergorgic Acid)的制备：海洋生物侧扁软柳珊瑚(Subergogia Suberosa)经过水洗、晒干、切碎、用95％乙醇浸泡。乙醇提取液减压浓缩后用石油醚(60-90℃)萃取，除去石油醚得棕黑色稠状物，经硅胶(60-100目)柱层析，然后用不同比例石油醚和乙酸乙酯混合液冲洗，可得到草绿色固体；草绿色固体在0℃时用石油醚洗去色素，在乙酸乙酯中结晶，即异柳珊瑚酸(Isosubergorgic Acid)，含量是干柳珊瑚重的0.0033％。
实施例2
异柳珊瑚酸(Isosubergorgic Acid)的物理性质：
1.薄层色谱(硅胶)：石油醚Rf＝0.05 石油醚∶乙酸乙酯＝1∶1 Rf＝0.5
2.熔点：174-174.5℃
3.旋光度：-143。(c.0.7 CHCl3)
4.溶解度(100克溶剂)：乙酸乙醋：7.2g 石油醚：0.7g
5.稳定性：a：在常温下保持4年，或在150℃下保持二小时其化学性质不变。
b：在水、有机溶剂(乙醇.氯仿.乙醚……)中其化学性质稳定
实施例3
异柳珊瑚酸的急性毒性LD50为68mg/Kg(腹腔注射)*：
剂量(mg/Kg) 40 48 58 70 84 100
死亡数 0 2 3 5 6 10
死亡率 0 0.20 0.30 0.50 0.60 1.00
*小鼠腹腔注射异柳珊瑚酸，观察毒性反应，小鼠在给药后3-5分钟即相继出流涎多汗、呼吸困难全身颤抖及惊厥等反应。严重的10分左死亡，轻的在数小时之后恢复正常。
实施例4
表一 异柳珊瑚酸和石杉碱甲的Y型迷宫实验 *
药物(mg/Kg) 动物数 学习成绩 记忆成绩
对照组** --- 10 2.4±1.43 2.1±1.10
石杉碱甲 0.12 10 2.2±1.23 1.2±0.79
异柳珊瑚酸 1.0 10 2.2±1.23 1.0±0.82
*小鼠(25g±2)，雌雄各半，以36V电压刺激，测定小鼠学习成绩(以连续二次正确为合格)，24小时后ip给药，15分钟后测定记忆成绩。
**溶剂对照组，给予1％吐温-80的生理盐水
实施例5
表二 不同浓度的异柳珊瑚酸对人红细胞AChE的抑制(百分数％)
异柳珊瑚酸的浓度 抑制反应时间
(mg/L) 30(min) 60(min) 90(min) 120(min)
0.2 40 32 29 35
2.0 55 55 53 44
20.0 91 88 88 88
*按Ellman氏方法(Biochemical Pharmacology，Vol.38，No.4 pp.633-640.1989)测定人红细胞胆碱酯酶(AChE)活性，pH＝7.0。
实施例6
表三 异柳珊瑚酸对人红细胞AChE的抑制作用(百分数％) 异柳珊瑚酸的浓度 抑制反应时间
(mg/L) 2(min) 3(min) 4(min) 5(min) 6(min) 7(min)
0.0002 21.4 22.7 16.4 22.6 14.5 14.8
*按Ellman氏方法(Biochemical Pharmacology，Vol.38，No.4 pp.633-640.1989)测定人红细胞胆碱酯酶(AChE)活性，pH＝7.0。
实施例7
表四 异柳珊瑚酸和敌敌畏对人血清BuChE的影响时间
对照组
敌敌畏 异柳珊瑚酸
(0.005mg/L) (0.2mg/L) (2mg/L) (20mg/L)60(min) 1 0.202±0.01 1.085±0.110 1.095±0.120 0.920±0.0790(min) 1 0.163±0.01 0.959±0.085 0.963±0.100 0.959±0.08120(min) 1 0.134±0.01 1.063±0.099 1.079±0.960 0.921±0.0724(h) 1 0.053±0.005 0.957±0.083 1.031±0.100 1.031±0.09
*按Ellman氏方法(Biochemical Pharmacology，Vol.38，No.4 pp.633-640.1989)测定人血清BuChE活性，pH＝7.0。
实施例8
表五 异柳珊瑚酸对SD鼠脑匀浆胆碱酯酶的抑制作用 *
脑匀浆体积(μl) 200 300 400 500
胆碱酯酶的抑制(％) 64％ 23％ 9％ 0％
*每毫升SD鼠脑匀浆液含15毫克脑；按Ellman氏方法(Biochemical Pharmacology，Vol.38，No.4 pp.633-640.1989)测定脑匀浆胆碱酯酶(AChE)活性，pH＝7.0。
Claims (2)
1、异柳珊瑚酸在制备乙酰胆碱酯酶抑制剂类药物中的应用。
2、根据权利要求1所述的应用，其特征在于异柳珊瑚酸在制备治疗阿尔茨海默病的药物中的应用。
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| WO2008031322A1 (fr) * | 2006-09-10 | 2008-03-20 | Shuping Hao | Application d'un médicament inhibiteur d'acétylcholine estérase à base d'un extrait de leonurus utilisé en tant que cholinomimétique |
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| WO2008031322A1 (fr) * | 2006-09-10 | 2008-03-20 | Shuping Hao | Application d'un médicament inhibiteur d'acétylcholine estérase à base d'un extrait de leonurus utilisé en tant que cholinomimétique |
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