X RAY MAPPING OF DOPAMINE D2 AGONISTS

本研究旨在“绘制”一系列多巴胺激动剂的三维结构和电子特性。特定的激动剂将从已知具有多巴胺能活性的化合物类别中选择。绘图将包括药物分子的整体几何形状，以及由净芳香电荷、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，将收集一组选择性D2多巴胺受体的多巴胺激动剂仔细测量的实验x射线衍射数据。选择用于电荷密度分析的特定化合物为：D2多巴胺受体。选择用于电荷密度分析的特定化合物有：(1)(+/-)-2-（n -苯乙基- n -丙基）氨基-5-羟四氢alin hydrochloride (PPHT)，一种非常有效的D2多巴胺激动剂。(2) R(-)-盐酸阿波啡，临床用于治疗帕金森病的化合物。(3)培高利特甲磺酸，一种麦角碱衍生物，用于治疗帕金森病。(4)溴隐碱甲磺酸盐是最广为人知的多巴胺能药物，用于纠正帕金森病左旋多巴治疗的长期并发症。(5)选择(-)-盐酸喹匹罗，因为它是一种选择性D2多巴胺受体激动剂。它在具有诱发性帕金森特征的猴子身上显示出抗震颤效果。一个分子模型研究包括一系列多巴胺激动剂已知结合D2受体提出。这项研究将包括确定分子的最低能量构象，从x射线晶体坐标或从Tripos片段库构建的结构开始。这些分子将被对接到一个蛋白质模型中，该模型包含了受体和药物分子之间静电相互作用的信息。

This study is designed to "map" the three dimensional structure and electronic character of a series of dopamine agonists. The specific agonists will be chosen from classes of compounds that are known to have dopaminergic activity. The mapping will include the overall geometry of the drug molecules as well as the electronic characteristics defined by the net aromic 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 selectivity for the D2 dopamine receptor. The specific compounds chosen for charge density analysis are: for the D2 dopamine receptor. The specific compounds chosen for charge density analysis are: (1)(+/-)-2-(N-phenlethyl-N-propyl)amino-5-hydroxytetralin hydrochloride (PPHT), a very potent D2 dopamine agonist. (2) R(-)-apomorphine hydrochloride, an compound used clinically in the treatment of Parkinson's disease. (3) pergolide methansulfonate, an ergoline derivative used in the treatment of Parkinson's disease. (4) bromocriptine methanesulfonate is the most widely known dopaminergic drug and is used to correct the long term complications of levodopa therapy in the treatment of Parkinson's disease (5) (-)-quinpirole hydrochloride was chosen because it is a selective D2 dopamine receptor agonist. It shows anti-tremor effects in monkeys with induced Parkinsonian traits. A molecular modeling study including a series of dopamine agonists known to bind to the D2 receptor is proposed. The study will involve determining the lowest energy conformation of the molecules beginning with the x-ray crystallographic coordinates or a structure build from the Tripos fragment library. The molecules will be docked into a protein model that contains information about the electrostatic interactions between the receptor and the drug molecules.