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  • Active compounds and were further


    Active compounds , , and were further tested and EC and pEC values were determined as shown in . Compound showed EC of 0.97μM (pEC 6.01) with 84.5% maximal response, which suggests that introduction of alkyl chain on aromatic nucleus of , resulted in improved GPR40 agonistic activity than that of (EC 6μM, pEC 5.22, 102.2% maximal response). Compound showed potent activity with EC value of 0.07±0.004μM (pEC 7.12, 100.2% maximal response). The efficacy of the compound is shown as a percentage of the maximal agonistic response elicited by the test compound with respect to the maximal response evoked by the internal standard (linoleic acid) at a dose of 10μM. In order to determine the selectivity, compound was also tested for hPPAR-γ agonistic activity and it showed very weak agonistic activity for hPPAR-γ. DMPK study on one of representative of the scaffold (compound ) was performed and pharmacokinetic parameters ( 0.25h, 0.88μg/mL, AUC 3–13hμg/mL, AUC 3.41hμg/mL and half-life 6.59h) showed that this scaffold has good PK properties. Activation of the GRP40 receptor is known to play a role in pancreatic and neurological function and the receptor is specifically localized in the brain and pancreas. In the pancreas the receptor expression is restricted to insulin producing β-cells. Since the key objective of GPR40 agonists is to prime islet β-cells to respond to glucose by inducing insulin secretion, we further evaluated these active compounds for their ability to induce insulin secretion in pancreatic islet cells. Further, the GPR40 mRNA is known to be expressed significantly in most pancreatic β-cell lines with highest expression levels in MIN6, followed by β-TC and HIT-T15. We therefore selected the HIT-T15 cell line for insulin secretion studies. HIT-T15 from hamsters were treated with 10μM of compound , and Each of these induced insulin secretion comparable to the effect of linoleic a-MSH, amide (). Further, the inactive compounds did not show any antagonist effect for linoleic acid induced calcium flux (data not included).
    INTRODUCTION Free fatty acids (FFAs) are essential dietary nutrients, and they also act as signaling molecules in various physiological processes. Nuclear receptors peroxisome proliferator-activated receptors (PPARs) and fatty acid binding proteins (FABPs) are known to function as sensors for FFAs and to contribute to various physiological conditions. However, the FFA effect on some biological processes might be mediated by other mechanisms such as signaling through cell surface receptors., In the last decade, a G-protein-coupled receptor (GPCR) deorphanizing strategy identified a series of receptors for FFAs. GPCRs are seven-transmembrane receptors, which activate heterotrimeric G proteins by ligand interactions, and they play important roles in various physiological processes. Thus, FFA receptors (FFARs) have attracted considerable attention due to their potential as valuable drug targets (Table 1). Among FFARs, FFAR2 (GPR43) and FFAR3 (GPR41) are receptors for short-chain fatty acids (SCFAs).5., 6., 7. Expression of FFAR2 has been detected in the immune cells, the gastrointestinal tract, and adipocytes, and it contributes to metabolic homeostasis and inflammatory responses.7., 8., 9. It has been reported that FFAR3 is expressed in the adipose tissue and the gastrointestinal tract, and stimulation of FFAR3 by short-chain FFAs induces secretion of leptin from adipocytes, suggesting that FFAR3 contributes to energy homeostasis. SCFAs are produced primarily through fermentation of dietary fibers in the intestine. Thus, these reports suggest that SCFAs act as signaling molecules that stimulate FFAR2 and FFAR3. On the other hand, FFAR1 and GPR120 are activated by medium- and long-chain FFAs. FFAR1 is detected primarily in pancreatic β-cells, and their physiological functions contribute to insulin secretion. GPR120 is reported to be expressed primarily in the intestine, adipocytes, and macrophages, and their physiological functions carried out by each of these tissues have been reported to contribute to the secretion of glucagon-like peptide-1 (GLP-1), adipocyte differentiation, and anti-inflammatory effects., Thus, these physiological functions are considered to be involved in metabolic disorders such as type 2 diabetes. Therefore, FFARs have received considerable attention as potential therapeutic targets for metabolic disorders. In this review, we focus on recent advances in our understanding of GPR40 and GPR120.