山莨宕碱的结构修饰与构效关系.docVIP

山莨宕碱的结构修饰与构效关系? 杨丽敏，钮因尧, 朱亮，谢一凡，顾雅芳，崔永耀，陈红专，陆阳*（上海交通大学医学院药学系，上海 200025） 摘要：目的 观察山莨宕碱衍生物的抗胆碱活性，总结其构效关系。方法 通过将山莨宕碱的羟基选择性地乙酰化，氮原子甲基化，制备山莨宕碱衍生物；利用波谱方法鉴定其结构；通过兔瞳孔实验和离体豚鼠回肠肌实验观察制备化合物的胆碱能活性。结果 制备了五个山莨宕碱衍生物（1-5），其中1，3，4和5是新化合物；兔瞳孔实验和离体豚鼠回肠肌实验显示1和5有明显的抗胆碱活性。结论 山莨宕碱及其衍生物的6?-羟基乙酰化，将导致其抗胆碱活性减弱或消失；氮原子季铵化，将使其抗胆碱活性增强。 关键词：山莨宕碱；抗胆碱；M-受体拮抗剂；构效关系 Structure Modification and Structure-Activity Relationship of Anisodamine YANG Li-min, NIU Yin-yao, ZHU Liang, XIE Yi-fan, GU Ya-fang, CUI Yong-yao， CHEN Hong-zhuan, LU Yang(Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China) ABSTRACT: OBJECTIVE To observe the anticholinergic activity of the derivatives of anisodamine and summarize the structure-activity relationship. METHODS The hydroxyl groups were selectively acetylated and N atom was methylated respectively to prepare the derivatives of anisodamine. The chemical structures were determined by IR, 1H NMR, MS. Using pupils of rabbits and ileal muscles of guinea pig, the anticholinergic activity of the compounds were tested. RESULTS Five derivatives of anisodamine were prepared and 1，3，4 and 5 were new compounds. Compounds 1 and 5 showed anticholinergic activity in mydriatic experiments of rabbits and tests of ileal muscles of guinea pig. CONCLUSION Anticholinergic activity may be weakened with acetylating of 6?-hydroxyl of anisodamine and strengthened when its tertiary amine changes into quaternary. KEY WORDS: anisodamine; Anticholinergic activity; muscarinic antagonist; SAR 山莨宕碱（anisodamine，图1）是从茄科植物唐古特山莨宕（Scopolia tangutica Maxim.）根中提取的生物碱，是临床上常用的外周抗胆碱药。山莨宕碱与阿托品、东莨宕碱等莨菪烷类药物在药理学上同属于抗胆碱药中的毒蕈碱样胆碱受体（Muscarinic cholinoceptor，简称M-受体）拮抗剂。它们的化学结构非常相近，均具有莨宕烷母核，且莨宕烷的3?位均为莨宕酸酯，所不同的只是莨宕烷6、7位取代基的差异。构效关系研究表明，此类莨菪烷生物碱的活性必需结构包括氮原子和3?位的莨宕酸酯，即莨菪烷中六元环（哌啶环）一侧的结构[1]。我们从旋花科植物包公藤(Erycibe obtusifolia Benth)中提取到的包公藤甲素(简称包甲素，图1)是一个具拟胆碱活性的莨宕烷类生物碱，为M-受体激动剂[2,3]。包甲素及其类似物的构效关系研究表明：此类莨菪烷生物碱拟胆碱活性必需结构为莨菪烷中五元环（吡咯环）一侧由6?-乙酰氧基与C6、C5、N构成的刚性的立体结构（图1，包甲素及其类似物虚线框内部分结构）[4-7]。我们注意