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

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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.