Development of Second Messenger, Trafficking, and Functional Assays for GPR119

描述（由申请人提供）：G蛋白偶联受体GPR119是一种最近被去蛋白化的受体，已成为治疗肥胖和2型糖尿病的一个有吸引力的靶点。最近在动物模型中的研究表明，激活GPR119可以改善葡萄糖稳态，同时积极调节食物摄入和体重增加。它主要在人类和大鼠的胰腺和肠道以及啮齿动物的大脑中表达。GPR119的激活促进肠L细胞分泌肠促胰岛素GLP1和胰腺β细胞分泌胰岛素，这两者都是调节葡萄糖稳态的关键成分。最近已经报道了GPR119的小分子调节剂，然而，这些分子在其信号特性和内源性配体油乙基乙醇酰胺（OEA）的胰岛素分泌方面存在差异，这使得它们不适合用于探究GPR119的生物学和功能。该申请的重点是开发与HTS兼容的GPR119的创新和新颖的分析方法，用于分类伪产物的二次筛选分析，用于评估化合物与两种结构相关的gprcrs的选择性的反筛选，以及用于阐明生理相关细胞类型中化合物的药理学的功能分析，以评估促进肠促胰岛素和胰岛素分泌的体外功效。这些检测被设计为发现用于探索GPR119生物学和功能的新型小分子探针的基石。

DESCRIPTION (provided by applicant): The G protein coupled receptor GPR119 is a recently deophanized receptor that has emerged as an attractive target for the treatment of obesity and Type 2 Diabetes Mellitus. Recent studies in animal models have demonstrated that activation of GPR119 improves glucose homeostasis while positively modulating both food intake and weight gain. It is expressed predominantly in the pancreas and gut of humans and rats and in rodent brain. Activation of GPR119 promotes secretion of the incretin GLP1 from intestinal L cells and insulin from pancreatic beta cells, both key components in regulating glucose homeostasis. Small molecule modulators of GPR119 have recently been reported however, these molecules differ with respect to their signaling properties and insulin secretion from the endogenous ligand Olethylethanolamide (OEA), rendering them unsuitable probes for the interrogation of GPR119 biology and function. The emphasis of this application is on developing innovative and novel assays for GPR119 that are HTS compatible, secondary screening assays to triage artifacts, counterscreens to assess selectivity of compounds versus two structurally related GPCRs and functional assays to elucidate pharmacology of compounds in physiologically relevant cell types to assess in vitro efficacy for promoting incretin and insulin secretion. These assays are designed to be the cornerstone for the discovery of novel small molecule probes to be used in the exploration of GPR119 biology and function. PUBLIC HEALTH RELEVANCE: The GPR119 receptor is expressed in the pancreas and gastrointestinal tract and has recently emerged as an attractive target for the treatment of obesity and Type 2 Diabetes Mellitus. This proposal seeks to develop a series of novel high throughput compatible cell-based functional assay to identify GPR119 selective ligands that can be used as molecular probes to interrogate GPR119 receptor function in normal physiological processes and disease states.