Development of GPR30-Selective Ligands

描述（由申请人提供）：雌激素是人体中重要的激素，调节许多组织的生长、发育和稳态。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。我们最近描述了七种跨膜G蛋白偶联雌激素受体GPR30的新功能。该受体可被经典雌激素受体ER1和ER2的激动剂和拮抗剂激活。直到最近，还没有已知的GPR30特异性配体，这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gpr30选择性激动剂G-1。该应用程序的具体目标是：1。结合虚拟筛选和生物分子筛选，根据目前已知的结合和激活GPR30的化合物，鉴定额外的GPR30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，GPR30结合选择性和活性的关键分子决定因素。2. 基于Aim 1的生物分子筛选结果和结构活性分析，合理设计和合成新型g -1基配体的小文库（每周期最多20个化合物）。本研究的目的是分离配体内部的激动作用和拮抗作用，并通过靶向合成化学进一步评价新型GPR30配体的SAR。3. 描述目标1和目标2中鉴定和合成的化合物的生物学功能。将采用一系列功能性生物测定来表征显示活性的化合物的生物效应。这些检测将包括细胞内信号分析，如钙动员、ERK和EGFR磷酸化和PI3K激活；更复杂的细胞分析，如转录激活、细胞迁移和增殖；以及使用小鼠模型进行的体内研究。了解配体与GPR30结合的药理学特征和结构-活性关系，对于发现针对该受体的新药至关重要，从而揭示该受体的潜在生理学，并为改善雌激素依赖性癌症的治疗开发治疗方法。公共卫生相关性：雌激素在正常和疾病生物学中起重要作用。我们已经描述了一种新的膜雌激素受体，可能在雌激素生物学中起作用。这项工作的目标是开发新的化合物，可以专门针对这种新的受体激活或抑制其活性，而不影响其他雌激素受体。

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. PUBLIC HEALTH RELEVANCE: Estrogen plays an important role in normal and disease biology. We have characterized a novel membrane estrogen receptor that likely plays a role in estrogen biology. The goal of this work is to develop novel compounds that can specifically target this new receptor to either activate or inhibit its activity without affecting other estrogen receptors.