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是最近脱ophanized的受体，其已成为治疗肥胖症和2型糖尿病的有吸引力的靶点。最近在动物模型中的研究表明，GPR119的激活改善葡萄糖稳态，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的活化促进肠促胰岛素GLP 1从肠L细胞和胰岛素从胰腺β细胞的分泌，这两种成分都是调节葡萄糖稳态的关键成分。然而，最近已经报道了GPR119的小分子调节剂，这些分子在它们的信号传导性质和胰岛素分泌方面与内源性配体羟乙基乙醇酰胺（OEA）不同，使得它们不适合用于询问GPR119生物学和功能的探针。本申请的重点是开发与HTS兼容的GPR119的创新性和新型测定法、分类人工产物的二次筛选测定法、评估化合物相对于两种结构相关GPCR的选择性的反筛选法以及阐明化合物在生理相关细胞类型中的药理学以评估促进肠促胰岛素和胰岛素分泌的体外功效的功能测定法。这些试验旨在成为发现用于探索GPR119生物学和功能的新型小分子探针的基石。 公共卫生相关性：GPR119受体在胰腺和胃肠道中表达，最近已成为治疗肥胖和2型糖尿病的有吸引力的靶点。该提案旨在开发一系列新的高通量相容的基于细胞的功能测定来鉴定GPR119选择性配体，其可用作分子探针来询问GPR119受体在正常生理过程和疾病状态中的功能。

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.