摘要/Abstract
摘要： 目的 ·建立莨菪烷类 M3受体拮抗剂的定量结构－活性关系（ quantitative structure-activity relationship，QSAR）模型，为后续高活性分子的设计提供指导。方法 ·以 3α-羟基莨菪烷（ J0）为起始物，通过对莨菪烷母核 C-3α位的结构进行改良，合成新莨菪烷类化合物（ J1～ J6）。选取富含 M3受体的豚鼠气道环为测试样本，通过离体组织功能实验，测试新莨菪烷类化合物对 M3受体的拮抗参数（antagonistic parameter，pA2）。利用新合成的和课题组原有的莨菪烷类化合物的 pA2建立 QSAR模型，通过分析该模型的能量场（立体场、静电场）对莨菪烷类化合物拮抗活性的影响，获得结构优化提示。结果 ·本研究共合成 6个新莨菪烷类化合物。上述化合物均可对 M3受体产生拮抗作用，其中 J4的拮抗活性最大（pA27.992）。QSAR 模型的交叉验证相关系数平方（q）为 0.585，非交叉2验证相关系数平方（ r2）为 0.993。结论 ·在化合物 C-3α位的 R取代基中，环上 π键的共轭程度较大且有 O或 N原子参与共轭时，可明显提高化合物的拮抗活性。
关键词: 慢性阻塞性肺疾病, 莨菪烷, M3受体拮抗剂, 定量结构－活性关系
Abstract:
Objective · To provide theoretical guidance for the design of molecules with high activitybuilding the quantitative structure-activity relationship (QSAR) model for tropane compounds as muscarinic M3 receptor antagonists. Methods · Six compounds (J1-J6) were prepared with 3α-hydroxy-tropane (J0) as the starting materialmodifying the structure in C-3α position of the tropane skeleton. The antagonistic activity of new tropane compounds to muscarinic M3 receptors on tracheal rings of guinea pigs was evaluatedfunctional assays in vitro. The antagonistic parameters (pA2) of new tropane compounds prepared in this paper and former studies were applied to construct the QSAR model. The information about structural optimization was acquiredanalyzing the effect of steric field and electrostatic field of model on activity of tropane compounds. Results · The six new tropane compounds showed obvious antagonistic activity against M3 receptors. Among them, J4 had the greatest activity (pA27.992). The cross-validation correlation coefficient squared (q2) and the non-cross-validated correlation coefficient squared (r2) of the QSAR model were 0.585 and 0.993, respectively. Conclusion · The antagonistic activity to muscarinic M3 receptors can be obviously improved, when the conjugating extent of π-bonds is large and O or N atoms participate in conjugation on the rings in the R-substituting group at C-3α position of the compounds. [Key words]chronic obstructive pulmonary disease (COPD); tropane; M3 receptor antagonist; quantitative structure-activity relationship (QSAR)
Key words: chronic obstructive pulmonary disease (COPD), tropane, M3 receptor antagonist, quantitative structure-activity relationship (QSAR)
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