Novel selective ligands for free fatty acid receptors GPR120 and GPR40

Abstract

GPR120 and GPR40 are G-protein-coupled receptors whose endogenous ligands are medium- and long-chain free fatty acids, and they are thought to play an important physiological role in insulin release. Despite recent progress in understanding their roles, much still remains unclear about their pharmacology, and few specific ligands for GPR120 and GPR40 besides medium- to long-chain fatty acids have been reported so far. To identify new selective ligands for these receptors, more than 80 natural compounds were screened, together with a reference compound MEDICA16, which is known to activate GPR40, by monitoring the extracellular regulated kinase (ERK) and [Ca(2+)](i) responses in inducible and stable expression cell lines for GPR40 and GPR120, respectively. MEDICA16 selectively activated [Ca(2+)](i) response in GPR40-expressing cells but not in GPR120-expressing cells. Among the natural compounds tested, grifolin derivatives, grifolic acid and grifolic acid methyl ether, promoted ERK and [Ca(2+)](i) responses in GPR120-expressing cells, but not in GPR40-expressing cells, and inhibited the alpha-linolenic acid (LA)-induced ERK and [Ca(2+)](i) responses in GPR120-expressing cells. Interestingly, in accordance with the pharmacological profiles of these compounds, similar profiles of glucagon-like peptide-1 secretion were seen for mouse enteroendocrine cell line, STC-1 cells, which express GPR120 endogenously. Taken together, these studies identified a selective GPR40 agonist and several GPR120 partial agonists. These compounds would be useful probes to further investigate the physiological and pharmacological functions of GPR40 and GPR120.

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.…”

Structure-Activity Relationships of GPR120 Agonists Based on a Docking Simulation

“…We used a stable cell line Flp-in GPR120 that was established previously (Hara et al, 2009b). Flp-in GPR120 cells and murine enteroendocrine STC-1 cells were cultured as described previously (Hirasawa et al, 2005;Hara et al, 2009b).…”

The oral lipid sensor GPR120 is not indispensable for the orosensory detection of dietary lipids in mice

“…Ϫ / Ϫ mice were subjected to 20 µmol/l LA or GA, a specifi c GPR120 partial agonist ( 29 ), and were analyzed using calcium imaging. LA triggered a similar induction of [Ca 2+ ] i both in TBCs from control and GPR120 Ϫ / Ϫ mice, indicating that GPR120 Ϫ / Ϫ and GPR120 +/+ mice display similar conditioned aversion to LA CTA is a learned reduction of hedonic value of a taste occurring when the taste experience is paired with a digestive malaise.…”