X-RAY MAPPING OF DOPAMINE UPTAKE SITES

本课题旨在对一系列多巴胺转运蛋白配体的三维结构和电子性质进行“定位”。映射将包括药物分子的整体几何形状以及由净原子电荷、电子密度分布、静电势和分子间相互作用能定义的电子特性。为了计算这些量，将收集一组选定的类似物的仔细测量的实验X射线衍射数据，这些类似物具有不同程度的多巴胺摄取抑制和受体亲和力。选择用于电荷密度分析的具体化合物为：（1）1-[2-（二苯基甲氧基）乙基]-4-（3-苯基丙基）-哌嗪二盐酸盐GBR 12，909）是一种对多巴胺转运蛋白具有选择性的化合物，其在低浓度下抑制可卡因结合，（2）苯扎托品甲磺酸盐是一种有效的多巴胺摄取抑制剂，其竞争性抑制GBR 12，909结合，（3）马吲哚是一种竞争性抑制GBR 12，909结合的多巴胺摄取抑制剂，（4）哌甲酯是一种众所周知的兴奋剂，其有效地并在一定程度上选择性地结合多巴胺转运蛋白。常规的X射线晶体结构的几个衍生物的可卡因，马吲哚，GBR，哌甲酯，和benztropine将完成，以确定这些分子的三维结构和构象。该信息与选择用于电荷密度分析的分子的电子结构一起将用于模拟可卡因受体位点。这将使我们清楚地了解在该位点发生的药物结合和作用的电荷分布和结构要求。

This project is designed to "map" thje three dimensional structure and electronic character of a series of dopamine transporter ligands. The mapping will include the overall geometry of the drug molecules as well as the electronic characteristics defined by net atomic charges, electron density distribution, electrostatic potentials, and intermolecular interaction energies. To calculate these quantities, carefully measured experimental x-ray diffraction data will be collected on a selected set of analogs with varying degrees of dopamine uptake inhibition and receptor affinity. The specific compounds chosen for charge density analysis are: (1) 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine dihydrochloride GBR 12,909) is a compound selective for the dopamine transporter that inhibits cocaine binding at low concentrations, (2) benztropine mesylate is a potent dopamine uptake inhibitor that competitively inhibits GBR 12,909 binding, (3) mazindol is a dopamine uptake inhibitor that competitively inhibits GBR 12,909 binding, (4) methylphenidate is a well-known stimulant that binds potently and somewhat selectively to the dopamine transporter. Routine x-ray crystal structures of several derivatives of cocaine, mazindol, GBR, methylphenidate, and benztropine will be completed in order to determine the three-dimensional structures and conformations of these molecules. This information in conjunction with the electronic structure of the molecules chosen for charge density analysis will be used to model the cocaine receptor site(s). This will give us a cleared understanding of the charge distribution and structural requirements for drug binding and action that occur at this site.