基于药物PK/PD关联探讨苯环壬酯对映体立体选择性作用机制

项目名称： 基于药物PK/PD关联探讨苯环壬酯对映体立体选择性作用机制

项目编号： No.81202577

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 李敬来

作者单位： 中国人民解放军军事医学科学院

项目金额： 24万元

中文摘要： 苯环壬酯为我国具有自主知识产权的一类创新药物，外消旋体上市后主要用于治疗晕动病。临床应用发现苯环壬酯具有明显的抗帕金森作用，效价高于常用药物苯海索，在震颤动物模型上，左旋体抗震颤效果明显优于右旋体；在小鼠抑郁模型上，右旋体抗抑郁效果明显，左旋体无效；在小鼠最大电休克发作模型上，消旋体抗癫痫作用明显优于左旋体和右旋体，效价高于苯妥英钠和苯巴比妥。以上研究表明苯环壬酯光学异构体具有不同甚至相反的药效作用，这可能与光学异构体的立体选择性代谢及在脑神经核团的立体选择性分布有关。为阐明苯环壬酯光学异构体产生不同药效作用的原因，本研究拟采用手性分离和稳定性同位素氚标记技术，探讨光学异构体立体选择性代谢及脑区分布，着重研究光学异构体作用靶标及神经生物学机制，通过药物动力学与药理学效应（PK/PD）关联研究，阐明苯环壬酯光学异构体不同药效作用的分子机制及药效学物质基础。

中文关键词： 苯环壬酯；药物动力学；立体选择性；对映体；药代/药效

英文摘要： Phencynonate was the innovative drug for the treatment of motion sickness after the listing of the racemate with independent intellectual property rights of China. Phencynonate exhibited obvious anti-Parkinson effect in clinical application, its potency higher than that of commonly used drugs trihexyphenidyl. In an animal model of tremor, the R(-) configuration is more active than the S(+) configuration. In a mouse model of depression, the S(+) configuration showed obvious anti-depression effect, the R(-) configuration is invalid. In mice shock attack model of maximal electroshock, racemic was significantly better than the R(-) configuration and S(+) configuration, its potency higher than that of Phenytoin sodium and Phenobarbital. The above studies have shown that the phencynonate enantiomers exhibit different and even opposite pharmacodynamics, which may be related with the stereoselective metabolism and stereoselective distribution in brain nuclei of the enantiomers. To clarify the reason of phencynonate optical isomers produce different pharmacodynamics, this study intends to investigate the stereoselective metabolism and brain region distribution of optical isomers with chiral separation and stability isotope labeling technique. By using PK/PD link model association with targets and the Neurobiological Me

英文关键词： Phencynonate；Pharmacokinetics；Stereoselective；Enantiomer；PK/PD