X RAY MODELING OF DOPAMINE AGONISTS

该项目旨在“映射”三维结构， 一系列多巴胺激动剂的电子特性。映射将 包括药物分子的总体几何形状以及 由净原子电荷定义的电子特性，电子 密度分布、静电势和分子间 相互作用能为了计算这些量，仔细测量 实验X射线衍射数据将收集在一组选定的 具有不同程度药理活性的多巴胺激动剂， 受体选择性这些化合物包括属于 氨基四氢萘、阿朴啡、麦角林、苯并氮杂卓和苯并吲哚类 化合物。选择用于电荷密度分析的特定化合物 为： (l)（+/-）-2-二丙氨基-6，7-二羟基-1，2，3，4-四氢萘 氢溴酸盐，一种最有效的多巴胺能氨基四氢萘 已知的衍生品 (2)R（-）-morphothebaine hydrochloride，a dopaminergic apophine derivative 具有混合的D1/D2受体选择性 (3)甲磺酸培高利特是一种麦角林衍生物， 帕金森病的治疗 (4)（+/-）-7，8-二羟基-3-烯丙基-1-苯基-2，3，4，5-四氢-1H-3- 盐酸苯氮卓，一种中枢作用的D1多巴胺激动剂。 (5)N-正丙基-6-羟基-1，2，3a，4，5，9 b-六氢-3H-苯并[e]吲哚，a 多巴胺受体激动剂，具有混合的D1/D2受体亲和力。 利用多巴胺激动剂的x射线晶体结构的结果 而不是在确定之前，关于三维的信息 将获得分子的结构和构象。这些数据 将被用来试图了解如何小结构 修饰可导致药理活性的根本改变。 为了超越简单的锁和钥匙模型， 从高分辨率实验确定的分子结构 X射线衍射测量允许更完整地描述 立体化学，构象和电子的要求， 多巴胺受体结合位点有待开发。

This project is designed to "map" the three dimensional structure and electronic character of a series of dopamine agonists. The mapping will include the overall geometry of the drug molecules as well as the electronic characteristics defined by the 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 dopamine agonists with varying degrees of pharmacological activity and receptor selectivity. These include compounds belonging to the aminotetralin, aporphine, ergoline, benzazepine, and benz[e]indole classes of compounds. The specific compounds chosen for charge density analysis are: (l) (+/-)-2-dipropylamino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide, one of the most potent dopaminergic aminotetralin derivatives known. (2) R(-)-morphothebaine hydrochloride, a dopaminergic aporphine derivative with mixed D1/D2 receptor selectivity. (3) pergolide methansulfonate, an ergoline derivative used in the treatment of Parkinson's disease. (4) (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine hydrochloride, a centrally acting D1 dopamine agonist. (5) N-n-propyl-6-hydroxy-1,2,3a,4,5,9b-hexahydro-3H-benz[e]indole, a dopamine agonist with mixed D1/D2 receptor affinity. Using the results from the x-ray crystal structures of dopamine agonists not before determined, information regarding the three dimensional structure and conformation of the molecules will be obtained. These data will be used in an attempt to understand how small structural modifications can result in radical changes in pharmacological activity. To progress beyond a simple lock and key model, adding the electronic structure of the molecules determined experimentally from high resolution x-ray diffraction measurements allows a more complete description of the stereochemical, conformational, and electronic requirements of the dopamine receptor binding sites to be developed.