Development Of Sulfonamide Small Molecule Fluorescent Probes For GPR120

GPR120,a member of the G protein coupled receptor family,expresses in liver,lung,intestine and adipose tissue at the tissue level,while at the cellular level,in macrophages,taste cells,enteroendocrine cells and adipocytes.Previous study found that GPR120 has beneficial effect on the treatment of type 2 diabetes,pulmonary dysfunction,cancers and so on.Through the use of GPR120 ligand studies,there was a variety of physiological mechanisms of GPR120,for example,promoting GLP-1 release,regulating multiple hormone secretion,mediating anti-inflammatory effects,and affecting lipid formation.However,some details about GPR120 are still unclear,it is of great significance to obtain a small molecule fluorescent probe that can study the physical mechanism of GPR120 pathology easily and sensitively.In this paper,a sulfonamide probe of GPR120 was synthesized and the pharmacological properties of the probe,the mechanism of action of GPR120,and the screening method of related ligands were well studied.When designing a small molecule fluorescent probe for detecting GPR120,this research aims at the structure of sulfonamide,rather than the selected carboxylic acid structure previously.In the early research of GPR120,a variety of carboxylic acid agonists were developed based on endogenous fatty acids,in which their molecular structures contain carboxylic acid groups.The disadvantage is that such agonists are also selective for GPR40.While the sulfonamide agonists reported in the literature have almost no activity for GPR40,we hope to design a non-acid GPR120 probe.In this research,the core structure of TUG-1197 was selected to approach a highly selective GPR120 probe with fluorophores of coumarin and naphthalimide.After evaluating the optical properties,cytotoxicity,and GPR120 activity of these probes,the localization and internalization of GPR120 was confirmed by probes.Through calcium influx experiments,we found that these probes are not selective in GPR40.Finally,we applied these probes to construct a screening method for GPR120 ligands.After comparing the quantification methods using FP,FI and BRET,the competitive selection method using BRET detection was finally selected to construct an activity screening method,which can rapidly screen agonists for GPR120.In summary,this study designed small molecule fluorescent probes for GPR120,which can provide a new method for the related research of GPR120 receptor.