中文摘要：

阿片受体激动剂与特定阿片受体亚型结合,常用来治疗与外伤、癌症或心脏病相关的严重疼痛,是十分有吸引力的药用物质.阿片受体有3种经典亚型（δ,κ,μ）,均有与其对应的激动剂.δ阿片受体（DOR）激动剂因其还有明显的抗焦虑、抗抑郁和器官保护作用,是非常有前景的药物.本文研究了一批共102个N-取代螺环哌啶类似物作为δ阿片受体激动剂的分子,采用比较分子力场（CoMFA）和比较分子相似性指数（CoMSIA）两种分析方法对所有分子进行了三维定量构效关系（3D-QSAR）研究,其中基于疏水场和氢键供体场参数建立的CoMSIA模型最佳,其模型结果为：Q^2=0.501,Rncv^2=0.787,Rpre^2=0.780,证明模型自我吻合良好,同时有较强的内部及外部预测能力.而模型的等势线图分析表明,在R1处引入疏水性的取代基及在R2处引入亲水性的取代基或氢键供体基团对提高激动剂活性有利.这些结论有助于更好地理解N-取代螺环哌啶类似物作为DOR激动剂的机理,为新型的δ阿片受体激动剂的设计和优化提供一定的指导.

英文摘要：

Opioid receptor （OPR） agonists which interact with specific subtypes of opioid receptors, are attractive pharmaceutical chemicals, and are extensively used in the treatment of severe pain associated with traumatic injuries, cancer or heart attacks. There are three typical subtypes of OPRs, i.e., δ, κ, and μ, which all have their respective agonists. Among them, δ-OPR （DOR） agonists are especially promising pharmaceutical chemicals for their additional anti-depressant and anti-anxiety as well as organ-protective abilities. To investigate the mechanism of δ-OPRs agonists and the receptor, in the present work 102 derivatives of N-substituted spiropiperdines were studied through three-dimensional quantitative structure-activity relationships （3D-QSAR） analysis. In conclusion, PLS analysis （Q^2=0.501, Rncv^2=0.787, Rpre^2=0.780） of the optimal CoMSIA model （yielded by hydrophobic and hydrogen-bond donor fields） manifesting good inter predictive capacity, excellent inter-consistency, and outstanding predictive ability, implies the rationality of the model. At the same time, the 3D-QSAR contour map analysis results indicate that the hydrophobic group substitution of R1 is beneficial to the activity of delta opioid agonists, and the hydrophilic or hydrogen-donor substitution of R2 is also favorable. These conclusions are helpful for understanding the mechanism of DOR agonists, as well as the guiding of design and improvement of new δ-OPR agonists in the future.