The first synthetic agonists of FFA2: Discovery and SAR of phenylacetamides as allosteric modulators

Wang, Yingcai; Jiao, Xiaojin; Kayser, Frank; Liu, Jiwen; Wang, Zhongyu; Wanska, Malgorzata; Greenberg, Joanne; Weiszmann, Jennifer; Ge, Hongfei; Tian, Hui; Wong, Simon; Schwandner, Ralf; Lee, TaeWeon; Li, Yang

doi:10.1016/j.bmcl.2009.11.112

Cited by 84 publications

(118 citation statements)

References 20 publications

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“…Simulations of 4-CMTB binding and unbinding suggested the ligand enters the receptor through the extracellular tips of helices 4 and 5, moves to the orthosteric site composed of S68 3.29 , Y90 3.33 , I145 4.61 , H242 6.55 and R180 5.39 and subsequently, with the help of the inter-site translator residues Y165 EL2 and Y90 3.33 , occupies the allosteric site by interacting with K65 2.60 . The obtained allosteric binding pose of 4-CMTB is consistent with the SAR studies Wang et al 2010). In the binding site the carbonyl group of the amide group of 4-CMTB forms H-bonding with K65 2.60 while the hydrogen of the amide group forms an H-bond with the backbone of C164 EL2 .…”

Section: Free Fatty Acid Receptorsupporting

confidence: 88%

“…In the binding site the carbonyl group of the amide group of 4-CMTB forms H-bonding with K65 2.60 while the hydrogen of the amide group forms an H-bond with the backbone of C164 EL2 . The importance of the amide group to act as a hydrogen bond acceptor and donor in binding of 4-CMTB to the receptor is confirmed by the absence of activity for analogues containing amino or methylamide groups Wang et al 2010). The isopropyl moiety of 4-CMTB sticks to helices 2 and 3 forming hydrophobic interactions with L61 2.56 , W75 EL1 , T85 3.28 , F89 3.32 and the hydrophobic tail of K65 2.60 .…”

Section: Free Fatty Acid Receptormentioning

confidence: 97%

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Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

Tikhonova

2016

Free Fatty Acid Receptors

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Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors. Analysis of the crystal structure and improved homology models, along with mutagenesis data and structure activity, highlighted an unusual arginine charge pairing interaction in FFA1-3 for receptor modulation, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84. Structural data will be helpful for searching novel small molecule modulators at the FFA receptors.

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Section: Free Fatty Acid Receptorsupporting

confidence: 88%

Section: Free Fatty Acid Receptormentioning

confidence: 97%

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

Tikhonova

2016

Free Fatty Acid Receptors

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“…The main endogenous SCFAs (C2, C3, and C4) activate FFA2 and FFA3 with varying potency (denoted by the thickness of the arrow), and the rank order of activity is not maintained between human and mouse species orthologs (Hudson et al, 2012b). Synthetic allosteric agonists at FFA2 are represented by phenylacetamides, where 4-CMTB is the most potent ligand (Lee et al, 2008;Wang et al, 2010;Smith et al, 2011) and it maintains its activity across human and mouse FFA2 (Hudson et al, 2012b). Allosteric modulators at FFA3 are represented by a class of synthetic ligands that comprise allosteric agonists, such as AR420626, and allosteric antagonists, such as 2-methyl-5-oxo-4-(3-phenoxyphenyl)-N-(o-tolyl)-1, 4,5,6,7,8-hexahydroquinoline-3-carboxamide (compound 6) .…”

Section: Ffa2/ffa3 Receptor Structure and Signal Transductionmentioning

confidence: 99%

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

et al. 2015

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Despite some blockbuster G protein-coupled receptor (GPCR) drugs, only a small fraction (∼15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2-6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation byproducts of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic b-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair.

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“…In particular, (S)-4-chloro--(1-methylethyl)-N-2-thiazolylbenzeneacetamide (14) was identified in a high throughput screen and found to be a selective ago-allosteric modulator of FFA2 [87]. As is often the case with allosteric ligands, subsequent attempts to explore the SAR of this series were unable to improve on its modest potency despite modification of all parts of the structure [88,89]. Defining the allosteric site where 14 binds has also presented a substantial challenge, with several modeling and mutagenesis studies unable to determine a precise mode of binding [88][89][90][91].…”

Section: Allosteric Ligands For Ffa2 and Ffa3mentioning

confidence: 99%

“…As is often the case with allosteric ligands, subsequent attempts to explore the SAR of this series were unable to improve on its modest potency despite modification of all parts of the structure [88,89]. Defining the allosteric site where 14 binds has also presented a substantial challenge, with several modeling and mutagenesis studies unable to determine a precise mode of binding [88][89][90][91]. Somewhat surprisingly, although significant species variation has been observed among the orthosteric SCFAs at FFA2, 14 appears to show little variation in potency and activity between human, rodent [83] and bovine (unpublished observation) orthologues of FFA2.…”

Section: Allosteric Ligands For Ffa2 and Ffa3mentioning

confidence: 99%

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

Hudson¹,

Ulven²,

Milligan

2013

CTMC

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G protein coupled receptors (GPCRs) are the most historically successful therapeutic targets. Despite this success there are many important aspects of GPCR pharmacology and function that have yet to be exploited to their full therapeutic potential. One in particular that has been gaining attention in recent times is that of GPCR ligands that bind to allosteric sites on the receptor distinct from the orthosteric site of the endogenous ligand. As therapeutics, allosteric ligands possess many theoretical advantages over their orthosteric counterparts, including more complex modes of action, improved safety, more physiologically appropriate responses, better target selectivity, and reduced likelihood of desensitisation and tachyphylaxis. Despite these advantages, the development of allosteric ligands is often difficult from a medicinal chemistry standpoint due to the more complex challenge of identifying allosteric leads and their often flat or confusing SAR. The present review will consider the advantages and challenges associated with allosteric GPCR ligands, and examine how the particular properties of these ligands may be exploited to uncover the therapeutic potential for free fatty acid sensitive GPCRs.

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The first synthetic agonists of FFA2: Discovery and SAR of phenylacetamides as allosteric modulators

Cited by 84 publications

References 20 publications

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

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

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