Development of GPR30-Selective Ligands

描述（由申请人提供）：雌激素是人体内调节许多组织生长、发育和体内平衡的关键激素。对雌激素的生理反应包括哺乳动物生殖和乳房功能、中枢神经和免疫系统、骨骼生理和血管功能的调节。我们最近描述了七跨膜G蛋白偶联雌激素受体GPR 30的新功能。该受体被经典雌激素受体ER 1和ER 2的激动剂和拮抗剂激活。直到最近，还没有已知的GPR 30的特异性配体，使得传统的药理学方法难以研究这种受体。然而，我们最近的研究结合了虚拟和生物分子筛选，发现了第一个GPR 30选择性激动剂G-1。本申请的具体目的是：1.进行虚拟和生物分子筛选的组合，以基于目前已知的结合和激活GPR 30的化合物来识别额外的GPR 30特异性配体。将进行结构-活性分析，以确定与经典雌激素受体相比，GPR 30结合选择性和活性的关键分子决定因素。2.基于目标1的生物分子筛选结果和构效关系分析，合理设计和合成小规模（每个循环多达20个化合物）的新型G-1配体库。该目的的目标是将配体内的激动作用与拮抗作用分开，并通过靶向合成化学进一步评价新型GPR 30配体的SAR。3.鉴定目标1和2中鉴定和合成的化合物的生物学功能。将采用功能性生物测定的集合来表征显示活性的化合物的生物效应。这些试验将包括细胞内信号传导试验，如钙动员、ERK和EGFR磷酸化和PI 3 K活化;更复杂的细胞试验，如转录活化、细胞迁移和增殖;以及使用小鼠模型的体内研究。了解配体与GPR 30结合的药理学特征和结构-活性关系对于发现靶向该受体的新型药物至关重要，其目的是揭示受体的潜在生理学，并开发用于改善雌激素依赖性癌症治疗的治疗方法。

DESCRIPTION (provided by applicant): Estrogen is a critical hormone in the human body that regulates the growth, development and homeostasis of many tissues. Physiological responses to estrogen include the regulation of mammalian reproduction and breast function, central nervous and immune systems, skeletal physiology and vascular function. We have recently described novel functions of the seven transmembrane G protein-coupled estrogen receptor, GPR30. This receptor is activated by both agonists and antagonists of the classical estrogen receptors, ER1 and ER2. Until recently there were no known specific ligands for GPR30, making traditional pharmacological approaches to the study of this receptor difficult. Our recent studies however have combined both virtual and biomolecular screening to discover the first GPR30-selective agonist, G-1. The specific aims of this application are: 1. Perform a combination of virtual and biomolecular screening to identify additional GPR30-specific ligands based on compounds presently known to bind and activate GPR30. Structure-activity analyses will be carried out to determine the critical molecular determinants for GPR30 binding selectivity and activity as compared to classical estrogen receptors. 2. Based on the biomolecular screening results and structure-activity analyses of Aim 1, rationally design and synthesize small libraries (up to 20 compounds per cycle) of novel G-1-based ligands. The goal of this aim is to separate agonism from antagonism within ligands, and to further evaluate the SAR of novel GPR30 ligands through targeted synthetic chemistry. 3. Characterize the biological functions of the compounds identified and synthesized in Aims 1 and 2. A collection of functional bioassays will be employed to characterize the biological effects of the compounds displaying activity. These assays will include intracellular signaling assays such as calcium mobilization, ERK and EGFR phosphorylation and PI3K activation; more complex cellular assays such as transcriptional activation, cell migration and proliferation; and in vivo studies using mouse models. Understanding the pharmacological profile and structure-activity relationships for ligand binding to GPR30 will be critical to the discovery of novel drugs that target this receptor for the purposes of revealing the underlying physiology of the receptor and developing therapeutic approaches for the improved treatment of estrogen-dependent cancers.