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New strategy for the drug development of CNS acting drugs by regulating drug transport across the blood-brain barrier

通过调节药物跨血脑屏障转运开发中枢神经系统药物的新策略

基本信息

批准号：
15390035
负责人：
SUGIYAMA Yuichi
金额：
$ 7.94万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390035/
关键词：
blood-brain barrier transporter efflux transport organic anion pharmacophore substrate specificity pharmacophore

项目摘要

The purpose of the present project was aimed at establishing a rational drug-design to overcome the efflux transport across the blood-brain barrier. In order to realize the goal, the substrate specificity of the efflux transporter was characterized by an in silico approach. Homology modeling predicted the 3-D structure model of rat organic anion transporter 3 using a glycerol transporter from E.Coli as template. In the 3-D structure model, the amino acid residues, which have been suggested to be important for substrate recognition and/or translocation, were found to be located in one region. Furthermore, the pharmacophore model of Oat3 substrates fitted to this arrangement of the amino acid residues, suggesting rationality of the 3-D structure model.The role of Oat3 in the blood-cerebrospinal fluid barrier was investigated. In addition to benzylpenicillin and p-aminohippurate, it was suggested that Oat3 is involved in the uptake of 2,4-dichlorophenoxyacetate (an organic herbicide) by the choroid plexus. Furthermore, although H_2 receptor antagonists, such as cimetidine, ranitidine and famotidine, are weak or cationic compounds at physiological pH, it was suggested that Oat3 accounts for their uptake by the choroid plexus. Calculation of molecular electrostatic potential of the H_2 receptor antagonists revealed that there is a region showing negative MEP in their chemical structures. This region may be important for the interaction of the H2 receptor antagonists with rOat3. Comparison of the intrinsic parameter revealed the species difference in the transport by rat and human OAT3. Therefore, it is difficult to predict pharmacokinetics in human from animal experiments for some compounds.

本项目旨在建立一种合理的药物设计，以克服通过血脑屏障的外排运输。为了实现这一目标，外排转运体的底物特异性通过计算机方法进行了表征。同源性建模以大肠杆菌甘油转运体为模板，预测大鼠有机阴离子转运体3的三维结构模型。在三维结构模型中，发现对底物识别和/或易位起重要作用的氨基酸残基位于一个区域。此外，Oat3底物的药效团模型符合氨基酸残基的这种排列方式，表明了三维结构模型的合理性。研究了Oat3在血-脑脊液屏障中的作用。除了青霉素和对氨基马齿酸外，燕麦3还参与脉络膜丛对2,4-二氯苯氧乙酸（一种有机除草剂）的吸收。此外，虽然H_2受体拮抗剂，如西咪替丁、雷尼替丁和法莫替丁，在生理pH值下是弱或阳离子化合物，但这表明它们被脉络丛吸收的原因是Oat3。H_2受体拮抗剂的分子静电电位计算表明，它们的化学结构中存在一个负MEP区。该区域可能是H2受体拮抗剂与rOat3相互作用的重要区域。本征参数的比较揭示了大鼠和人在OAT3转运中的物种差异。因此，从动物实验中预测某些化合物在人体内的药代动力学是困难的。