Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists

Bharate, Sandip B.; Rodge, Atish H.; Joshi, Rajendra K.; Kaur, Jaspreet; Srinivasan, Shaila; Kumar, Sanjeev; Kulkarni-Almeida, Asha; Balachandran, Sarala; Balakrishnan, Arun; Vishwakarma, Ram A.

doi:10.1016/j.bmcl.2008.10.085

Cited by 37 publications

(22 citation statements)

References 21 publications

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“…Because uncharged amide and substituted amide derivatives of FFA1 carboxylic acid ligands do not have dramatically reduced potencies (Garrido et al, 2006) and certain diacyl phloroglucinols are also FFA1 agonists (Bharate et al, 2008), it is possible that one or more of these binding modes does not necessarily involve a direct interaction of the ligand with an arginine residue.…”

Section: Discussionmentioning

confidence: 99%

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

et al. 2012

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Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium-and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radioligand binding interaction studies revealed that the full agonists do not bind to the same site as the partial agonists but exhibit positive heterotropic cooperativity. Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo. Furthermore, the endogenous fatty acid docosahexaenoic acid (DHA) shows negative or neutral cooperativity with members of both series of agonists in binding assays but displays positive cooperativity in functional assays. Another synthetic agonist is allosteric with members of both agonist series, but apparently competitive with DHA. Therefore, there appear to be three allosterically linked binding sites on FFA1 with agonists specific for each of these sites. Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation. These ligands with their high potencies and strong positive functional cooperativity with endogenous fatty acids, demonstrated in vitro and in vivo, have the potential to deliver therapeutic benefits.

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Section: Discussionmentioning

confidence: 99%

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

et al. 2012

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“…Specific attention to its potential as a therapeutic target for the treatment of type 2 diabetes was driven by a combination of the known effect of fatty acids to elevate glucose-dependent insulin secretion and expression of FFA1 receptor mRNA in the insulin-producing ␤-cells of the pancreas (1,2). This has resulted in the search for, and identification of, novel and selective ligands for FFA1 via both traditional function-based screening of chemical libraries (11)(12)(13)(14)(15) and virtual screening of the receptor based on the generation of receptor homology and pharmacophore models (16). Studies using both knockdown of FFA1 levels in pancreatic cell lines (2,20,44,45) and FFA1 knock-out lines of mice (15,17,46,47) have provided further support for this receptor as an important regulator of insulin secretion and in the effects of fatty acids.…”

Section: Discussionmentioning

confidence: 99%

“…Coupled with the long appreciated effects of fatty acids to elevate glucose-dependent insulin secretion, this suggested FFA1/ GPR40 as a potential target for the treatment of diabetes (7)(8)(9)(10). This has resulted in efforts to identify small molecule ligands able to act as selective agonists or antagonists of FFA1 (11)(12)(13)(14)(15)(16) to act as tool compounds and the generation of knockout lines of mice (15,(17)(18)(19) to explore the physiological function of FFA1. FFA1 expression has also been detected in various pancreatic-derived cell lines, including MIN6, ␤-TC-3, HIT-T15, and INS-1E (1)(2)(3)20), and such lines have also, therefore, been used widely to explore the function of this receptor.…”

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confidence: 99%

The Action and Mode of Binding of Thiazolidinedione Ligands at Free Fatty Acid Receptor 1

Smith¹,

Stoddart

Devine

et al. 2009

Journal of Biological Chemistry

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The endogenous ligands for free fatty acid receptor 1 (FFA1) are medium and longer chain free fatty acids. However, a range of selective, small molecule ligands have recently been developed as tool compounds to explore the therapeutic potential of this receptor, whereas clinically employed thiazolidinedione "glitazone" drugs are also agonists at FFA1. Each of these classes of agonist was able to promote phosphorylation of the ERK1/2 mitogen-activated protein (MAP) kinases in cells able to express human FFA1 on demand. However, although both lauric acid and the synthetic agonist GW9508X produced rapid and transient ERK1/2 MAP kinase phosphorylation, the thiazolidinedione rosiglitazone produced responses that were sustained for a substantially longer period. Despite this difference, the effects of each ligand required FFA1 and were transduced in each case predominantly via G proteins of the G␣ q /G␣ 11 family. Different glitazone drugs also displayed markedly different efficacy and kinetics of sustainability of ERK1/2 MAP kinase phosphorylation. A number of orthosteric binding site mutants of FFA1 were generated, and despite variations in the changes of potency and efficacy of the three ligand classes in different functional end point assays, these were consistent with rosiglitazone also binding at the orthosteric site. Four distinct polymorphic variants of human FFA1 have been described. Despite previous indications that these display differences in function and pharmacology, they all responded in entirely equivalent ways to lauric acid, rosiglitazone, and GW9508X in measures of ERK1/2 MAP kinase phosphorylation, enhancement of binding of [ Fatty acids have long been known to produce a variety of effects in the body. However, until recently, these actions were thought to be mediated exclusively via regulation of cellular metabolism. Thus, the recent identification and deorphanization (1-5) of the free fatty acid (FFA) 3 family (reviewed in Refs. 6 and 7) of G protein-coupled receptors (GPCRs) has prompted re-evaluation of the mechanism of action of FFAs in health and disease. The initial deorphanization studies of free fatty acid receptor 1 (FFA1 4 ), which at that time was designated GPR40 (1-3), also demonstrated expression of receptor mRNA in the pancreas, and further analysis showed levels to be enriched in islets and, in particular, the insulin-producing ␤-cells (1, 2). Coupled with the long appreciated effects of fatty acids to elevate glucose-dependent insulin secretion, this suggested FFA1/ GPR40 as a potential target for the treatment of diabetes (7-10). This has resulted in efforts to identify small molecule ligands able to act as selective agonists or antagonists of FFA1 (11-16) to act as tool compounds and the generation of knockout lines of mice (15,(17)(18)(19) to explore the physiological function of FFA1. FFA1 expression has also been detected in various pancreatic-derived cell lines, including MIN6, ␤-TC-3, HIT-T15, and INS-1E (1-3, 20), and such lines have also, therefore, been used widely to ...

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“…Compared with the increasing number of reported FFAR1 ligands (Briscoe et al, 2003;Tikhonova et al, 2007;Bharate et al, 2008;Davi and Lebel, 2008;Hirasawa et al, 2008; …”

Section: Introductionmentioning

confidence: 99%

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

Sun

Hirasawa²,

Hara³

et al. 2010

Mol Pharmacol

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GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor ␥ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds (R 2 ϭ 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.

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Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists

Cited by 37 publications

References 21 publications

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

The Action and Mode of Binding of Thiazolidinedione Ligands at Free Fatty Acid Receptor 1

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

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