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.
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.
| Bohn, Laura M; McDonald, Patricia H (2010) Seeking Ligand Bias: Assessing GPCR Coupling to Beta-Arrestins for Drug Discovery. Drug Discov Today Technol 7:e37-e42 |
