X RAY MAPPING OF DOPAMINE D2 AGONISTS

本研究旨在对一系列多巴胺受体激动剂的三维结构和电子性质进行“定位”。特定激动剂将选自已知具有多巴胺能活性的化合物类别。映射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。为了计算这些量，将收集对D2多巴胺受体具有选择性的一组多巴胺激动剂的仔细测量的实验X射线衍射数据。选择用于电荷密度分析的特定化合物为：D2多巴胺受体。选择用于电荷密度分析的具体化合物为：（1）（+/-）-2-（N-苯乙基-N-丙基）氨基-5-羟基四氢萘盐酸盐（PPHT），一种非常有效的D2多巴胺激动剂。(2)R（-）-阿扑吗啡盐酸盐，临床上用于治疗帕金森氏病的化合物。(3)甲磺酸培高利特，一种用于治疗帕金森病的麦角林衍生物。(4)溴隐亭甲磺酸盐是最广为人知的多巴胺能药物，用于纠正帕金森病治疗中左旋多巴疗法的长期并发症。（5）选择（-）-盐酸喹吡罗是因为它是选择性D2多巴胺受体激动剂。它在具有诱发帕金森病特征的猴子中显示出抗震颤作用。提出了一种分子建模研究，包括一系列已知与D2受体结合的多巴胺激动剂。该研究将涉及确定分子的最低能量构象，从X射线晶体学坐标或从Tripos片段库构建的结构开始。这些分子将对接到一个蛋白质模型中，该模型包含有关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.