Development Of Agonists And Small-molecule Fluorescence Probes For GPR120

As one of the excellent member of G protein-coupled receptors(GPCRs),GPR120(G protein-coupled receptor 120)mainly expresses inliver,intestinal tract and adipose tissue,which mediates multiple physiological functions(e.g.,GLP-1 secretion,anti-inflammatory,insulin sensitization and anti-obesity)and is related with many physiological diseases,such as type 2 diabetes,diet and obesity.Therefore,theexamination of pharmacological and pathological role for GPR120 by using a small-molecule toolkitis of vital significance in pathogenesis and treatment type 2 diabetes or obesity.In this study,we designed and evaluated seven small-molecular fluorescent probes for the GPR120.As well as,a series of aromatic acid agonists as followings:(1)Small molecule fluorescent probes for GPR120In recent years,fluorescent GPCR ligands have been widely applied to locate the distribution of receptors and to monitor the processes triggered by ligand-receptor interactions(e.g.,internalization,transport,sequestration and recycling)in a real-time manner.However,there'sfew report for detecting the distribution of GPR120 on the cell surfaceby usinga small-molecule fluorescent probe.Because of high sensitivity,selectivity,visualization and rapid response of small-molecule fluorescent probes,it is urgent to develop a convenient fluorescent ligand to track GPR120 to fully understand the physiological and pathologic functions of GPR120.In general,small molecule fluorescent probes consist of three moieties:fluorophore,linkers,and recognition group.To obtain high sensitive and selective small-molecule fluorescent probes for GPR120,we selected the essential components of TUG-891 and GW9508,which are well-knownthe agonists of GPR120,as the recognition moiety.In addition,naphthalimide and coumarin groups with excellent fluorescent properties,were chemically linked to the recognition moiety by aliphatic spacers.Finally,seven small-molecule fluorescent probes were well designed and evaluated for contributing to the biological and pharmacological research of GPR120.Subsequently,the optical properties,BRET assay,calcium assay,cell fluorescence imaging and cytotoxicity test were well measured.The experimental results revealed that these synthesized fluorescent probes for GPR120 displayed reasonable bioactivity,high selectivity,low cytotoxicity and successful feasibility in cell imaging.Therefore,these fluorescent probes can be used as a marker for GPR120 to provide detailed information on the physiological and pathological functions of GPR120.In addition,we expect that these probes can be used as competitive fluorescent substrates in GPR120 ligand screening for a rapid evaluation platform.(2)Small-molecular agonists for GPR120It has been reported that GPR120 agonism,which regulates the lipidformation,gastrointestinal peptide secretion,taste preference and glucose metabolism balance,can ameliorate inflammation,diabetes and other related metabolic health.Therefore,the development of GPR120 agonists will serve as a new option for the treatment of impaired metabolic diseases such as obesity,type 2 diabetes and cardiovascular disease.In this subject,a series of agonists for the GPR120 were well designed and evaluated.Compound 11 was identified as an effective GPR120 agonist with similar molecular mechanisms to the positive control TUG-891,which resulted in intracellular calcium response,P-arrestin 2 recuitment and the rapid internalization of receptor.In addition,compound 11 is expected to be serve as an important pharmacological tool to explore the relevant biological functions of GPR120 for treating obesity,type 2 diabetes and other metabolic diseases.In summary,development of small-molecule agonists and fluorescent probes for GPR120 will provide a new research tool for the study of GPR120 receptor so as to afford a solid theoretical guidance for further structural modifications.