Identification of G protein-coupled receptor 120-selective agonists derived from PPARγ agonists

Abstract

A weak, nonselective G protein-coupled receptor 120 (GPR120) agonist 10 was found by screening a series of carboxylic acids derived from the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist 3. Modification based on the homology model of GPR120 led to the first GPR120-selective agonist 12. These results provide a basis for constructing new tools for probing the biology of GPR120 and for developing new candidate therapeutic agents.

New Frontiers in Gut Nutrient Sensor Research: Free Fatty Acid Sensing in the Gastrointestinal Tract

“…Utilizing specific antibodies and knockout mice, we identified novel tissue distributions of the FFAR1 and GPR120 proteins (27,28,33). In addition, we and other groups discovered selective ligands for these FFARs (7,11,25,26). Further studies using specific antibodies, knockout mice, and selective agonists might reveal novel physiological roles of these FFARs in energy homeostasis.…”

“…Recently, we have succeeded in the synthesis of GPR120-selective agonist (25) and in identifying the gliforin derivatives as selective natural GPR120 partial agonists (26). These results provide a basis for the construction of new tools to probe the biology of GPR120 and for the development of new candidates for therapeutic agents.…”

The Therapeutic Potential of Allosteric Ligands for Free Fatty Acid Sensitive GPCRs

“…Interestingly, none of the key positively charged amino acids associated with fatty acid binding to the FFA1-3 family members are conserved in GPR120. Instead, each of the models identified one alternate arginine at position 2.64 as being responsible for a key ionic interaction with the carboxylate head group of the ligand [100,101,102]. The importance of R2.64 to the binding and/or function of both endogenous fatty acids [103] and 18 [101] has now been verified by mutagenesis.…”

“…(5)). The first of these reported a low potency ligand (17) with poor selectivity based on carboxylic acid derivatives of PPAR agonists [100], while the second described a significantly more potent and selective ligand (18) derived from a previously described series of FFA1 agonists [101]. Given the lack of sequence similarity between GPR120 and FFA1 it is perhaps surprising that a wider range of selective and potent compounds has not been described.…”

“…The orthosteric binding pocket of GPR120 has been examined in some detail, primarily through homology modeling [100,101,102]. Interestingly, none of the key positively charged amino acids associated with fatty acid binding to the FFA1-3 family members are conserved in GPR120.…”