X-RAY MAPPING OF DOPAMINE UPTAKE SITES

本项目旨在“绘制”一系列多巴胺转运体配体的三维结构和电子特性。绘图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。为了计算这些数量，将收集一组具有不同程度多巴胺摄取抑制和受体亲和力的类似物的仔细测量的实验x射线衍射数据。选择用于电荷密度分析的特定化合物有：（1) 1-[2-（二苯基甲氧基）乙基]-4-（3-苯丙基）-哌嗪二盐酸GBR 12909）是一种选择性的多巴胺转运体化合物，在低浓度下抑制可卡因结合，(2)甲磺酸苯托品是一种有效的多巴胺摄取抑制剂，竞争性地抑制GBR 12909结合，(3)mazindol是一种多巴胺摄取抑制剂，竞争性地抑制GBR 12909结合。(4)哌醋甲酯是一种众所周知的兴奋剂，它可以选择性地与多巴胺转运体结合。为了确定这些分子的三维结构和构象，将完成可卡因、马辛多、GBR、哌醋甲酯和苯托品的几种衍生物的常规x射线晶体结构。这些信息与电荷密度分析所选择的分子的电子结构相结合，将用于对可卡因受体位点进行建模。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.