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

本课题的目的是建立一种合理的药物设计，以克服跨血脑屏障的外排转运。为了实现这一目标，通过计算机模拟方法表征了外排转运蛋白的底物特异性。以大肠杆菌甘油转运蛋白为模板，同源模建预测了大鼠有机阴离子转运蛋白3的三维结构模型。在3-D结构模型中，被认为对底物识别和/或转运重要的氨基酸残基被发现位于一个区域中。Oat 3底物的药效团模型与氨基酸残基的这种排列方式相吻合，表明该三维结构模型是合理的。除了苄青霉素和对氨基马尿酸盐外，Oat 3还参与脉络丛对2，4-二氯苯氧乙酸盐（一种有机除草剂）的吸收。此外，尽管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下是弱或阳离子化合物，但有人认为Oat 3是脉络丛吸收它们的原因。H_2受体拮抗剂的分子静电势计算结果表明，在其化学结构中存在负MEP区。该区域对于H2受体拮抗剂与rOat 3的相互作用可能是重要的。内在参数的比较揭示了大鼠和人OAT 3转运的种属差异。因此，很难从动物实验中预测某些化合物在人体内的药代动力学。

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.