X RAY MODELING OF DOPAMINE AGONISTS

多巴胺激动剂的 X 射线建模

• 批准号: 6107009
• 负责人: Cheryl L Klein Stevens
• 金额: $ 19.39万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107009
• 关键词: X ray crystallography; analog; benzazepines; bioimaging /biomedical imaging; chemical models; chemical structure function; computer simulation; conformation; dopamine agonists; dopamine receptor; electron density; ergolines; indoles; intermolecular interaction; model design /development; molecular orbital; quantum chemistry

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.

该项目旨在绘制三维结构图，并 一系列多巴胺激动剂的电子特性。映射将 包括药物分子的整体几何构型以及 电子特性由原子净电荷、电子 密度分布、静电势和分子间相互作用 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和 受体选择性。这些化合物包括属于 氨基四氢呋喃、阿朴吗啡、麦角林、苯扎西平和苯并吲哚类 一种化合物。选择用于电荷密度分析的特定化合物 包括： (L)(+/-)-2-dipropylamino-6，7-dihydroxy-1，2，3，4-tetrahydronaphthalene 氢溴酸，最有效的多巴胺能氨基四氢化合物之一 已知的衍生产品。 (2)R(-)-吗啡盐酸盐，多巴胺能阿朴吗啡衍生物 具有混合的D1/D2受体选择性。 (3)甲磺酸培高利特，一种麦角林衍生物，用于 帕金森氏症的治疗。 (4)(+/-)-7，8-dihydroxy-3-allyl-1-phenyl-2，3，4，5-tetrahydro-1H-3- 盐酸苯扎西平，一种中枢作用的D1多巴胺激动剂。 (5)N-n-propyl-6-hydroxy-1，2，3a，4，5，9b-hexahydro-3H-benz[e]indole，a 具有混合D1/D2受体亲和力的多巴胺激动剂。 使用来自多巴胺激动剂的x射线晶体结构的结果 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 将被用来试图理解结构有多小 修饰可以导致药理活性的根本改变。 超越简单的锁和钥匙模型，添加电子 由高分辨率实验确定的分子结构 X射线衍射测量可以更完整地描述 的立体化学、构象和电子要求 有待开发的多巴胺受体结合部位。