The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism

Molecular Pharmacology

Volumn 84, Issue 5, 2013, Pages 710-725

  Hudson, Brian D ^a   Shimpukade, Bharat ^b   Mackenzie, Amanda E ^a   Butcher, Adrian J ^c   Pediani, John D ^a   Christiansen, Elisabeth ^b   Heathcote, Helen ^a   Tobin, Andrew B ^c   Ulven, Trond ^b   Milligan, Graeme ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

^b UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^c UNIVERSITY OF LEICESTER   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3 [4 [[4 FLUORO 4' METHYL (1,1' BIPHENYL) 2 YL]METHOXY]PHENYL]PROPANOID ACID; 4 [4 [2 (PHENYL 2 PYRIDINYLAMINO)ETHOXY]PHENYL]BUTYRIC ACID; 4 [[(3 PHENOXYPHENYL)METHYL]AMINO]BENZENEPROPANOIC ACID; ARGININE; BETA ARRESTIN 1; BETA ARRESTIN 2; DOXYCYCLINE; EPIDERMAL GROWTH FACTOR RECEPTOR; G PROTEIN COUPLED RECEPTOR 120; GEFITINIB; GLUCAGON LIKE PEPTIDE 1; GW 9508; LINOLENIC ACID; MITOGEN ACTIVATED PROTEIN KINASE; NCG 21; SMALL INTERFERING RNA; TUG 891; UNCLASSIFIED DRUG;

ADIPOCYTE; ANIMAL CELL; ARTICLE; BIOLUMINESCENCE RESONANCE ENERGY TRANSFER; CELL LINE; CELL SURFACE; CONFOCAL MICROSCOPY; CONTROLLED STUDY; ENTEROENDOCRINE CELL; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; FLUORESCENCE MICROSCOPY; GENE EXPRESSION; GENE SILENCING; GLUCOSE TRANSPORT; HUMAN; HUMAN CELL; INTERNALIZATION; MACROPHAGE; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PRIORITY JOURNAL; RECEPTOR DOWN REGULATION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION;

3T3-L1 CELLS; ANIMALS; ARRESTINS; BIPHENYL COMPOUNDS; CALCIUM; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; GLUCOSE; GTP-BINDING PROTEIN ALPHA SUBUNITS, GQ-G11; HEK293 CELLS; HUMANS; MICE; PHENYLPROPIONATES; PHOSPHORYLATION; RECEPTORS, G-PROTEIN-COUPLED;

EID: 84886060164     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.113.087783     Document Type: Article

References (41)

1. Bartoschek S, Klabunde T, Defossa E, Dietrich V, Stengelin S, Griesinger C, Carlomagno T, Focken I, and Wendt KU (2010) Drug design for G-proteincoupled receptors by a ligand-based NMR method. Angew Chem Int Ed Engl 49:1426-1429.
2. Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, McCoy DC, Kenakin TP, Andrews JL, and Ammala C et al. (2006) Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. Br J Pharmacol 148:619-628. (Pubitemid 43993052)
3. Burant CF, Viswanathan P, Marcinak J, Cao C, Vakilynejad M, Xie B, and Leifke E (2012) TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 379:1403-1411.
4. Burns RN and Moniri NH (2010) Agonism with the omega-3 fatty acids alphalinolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human GPR120 receptor. Biochem Biophys Res Commun 396:1030-1035.
5. Christiansen E, Due-Hansen ME, Urban C, Grundmann M, Schröder R, Hudson BD, Milligan G, Cawthorne MA, Kostenis E, and Kassack MU et al. (2012) Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties. J Med Chem 55:6624-6628.
6. Edfalk S, Steneberg P, and Edlund H (2008) Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57:2280-2287.
7. Fukunaga S, Setoguchi S, Hirasawa A, and Tsujimoto G (2006) Monitoring ligandmediated internalization of G protein-coupled receptor as a novel pharmacological approach. Life Sci 80:17-23. (Pubitemid 44809297)
8. Gotoh C, Hong YH, Iga T, Hishikawa D, Suzuki Y, Song SH, Choi KC, Adachi T, Hirasawa A, and Tsujimoto G et al. (2007) The regulation of adipogenesis through GPR120. Biochem Biophys Res Commun 354:591-597. (Pubitemid 46161365)
9. Gregory KJ, Hall NE, Tobin AB, Sexton PM, and Christopoulos A (2010) Identification of orthosteric and allosteric site mutations in M2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias. J Biol Chem 285:7459-7474.
10. Gregory KJ, Sexton PM, Tobin AB, and Christopoulos A (2012) Stimulus bias provides evidence for conformational constraints in the structure of a G proteincoupled receptor. J Biol Chem 287:37066-37077.
11. Groeger AL, Cipollina C, Cole MP, Woodcock SR, Bonacci G, Rudolph TK, Rudolph V, Freeman BA, and Schopfer FJ (2010) Cyclooxygenase-2 generates antiinflammatory mediators from omega-3 fatty acids. Nat Chem Biol 6:433-441.
12. Hara T, Hirasawa A, Sun Q, Sadakane K, Itsubo C, Iga T, Adachi T, Koshimizu T-A, Hashimoto T, and Asakawa Y et al. (2009a) Novel selective ligands for free fatty acid receptors GPR120 and GPR40. Naunyn Schmiedebergs Arch Pharmacol 380:247-255.
13. Hara T, Hirasawa A, Sun Q, Koshimizu T-A, Itsubo C, Sadakane K, Awaji T, and Tsujimoto G (2009b) Flow cytometry-based binding assay for GPR40 (FFAR1; free fatty acid receptor 1). Mol Pharmacol 75:85-91.
14. Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, and Tsujimoto G (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 11:90-94. (Pubitemid 40215843)
15. Holliday ND, Watson S-J, and Brown A J H (2011) Drug discovery opportunities and challenges at g protein coupled receptors for long chain free Fatty acids. Front Endocrinol (Lausanne) 2:112.
16. Hudson BD, Christiansen E, Tikhonova IG, Grundmann M, Kostenis E, Adams DR, Ulven T, and Milligan G (2012a) Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs. FASEB J 26:4951-4965.
17. Hudson BD, Due-Hansen ME, Christiansen E, Hansen AM, Mackenzie AE, Murdoch H, Pandey SK, Ward RJ, Marquez R, and Tikhonova IG et al. (2013a) Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J Biol Chem 288:17296-17312.
18. Hudson BD, Smith NJ, and Milligan G (2011) Experimental challenges to targeting poorly characterized GPCRs: uncovering the therapeutic potential for free fatty acid receptors. Adv Pharmacol 62:175-218.
19. Hudson BD, Tikhonova IG, Pandey SK, Ulven T, and Milligan G (2012b) Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3. J Biol Chem 287:41195-41209.
20. Hudson BD, Ulven T, and Milligan G (2013b) The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs. Curr Top Med Chem 13:14-25.
21. Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, and Iida K et al. (2012) Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483:350-354.
22. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, and Uejima H et al. (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422:173-176. (Pubitemid 36362750)
23. Kaku K, Araki T, and Yoshinaka R (2013) Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes. Diabetes Care 36:245-250.
24. Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, Moorhead JF, and Varghese Z (2005) EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism. Kidney Int 67:867-874. (Pubitemid 41623311)
25. Luo J, Swaminath G, Brown SP, Zhang J, Guo Q, Chen M, Nguyen K, Tran T, Miao L, and Dransfield PJ et al. (2012) A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. PLoS ONE 7:e46300.
26. Mobraten K, Haug TM, Kleiveland CR, and Lea T (2013) Omega-3 and omega-6 PUFAs induce the same GPR120-mediated signalling events, but with different kinetics and intensity in Caco-2 cells. Lipids Health Dis 12:101.
27. Negoro N, Sasaki S, Mikami S, Ito M, Tsujihata Y, Ito R, Suzuki M, Takeuchi K, Suzuki N, and Miyazaki J et al. (2012) Optimization of (2, 3-dihydro-1-benzofuran-3-yl) acetic acids: discovery of a non-free fatty acid-like, highly bioavailable G protein-coupled receptor 40/free fatty acid receptor 1 agonist as a glucose-dependent insulinotropic agent. J Med Chem 55:3960-3974.
28. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, and Olefsky JM (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142:687-698.
29. Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lichtarge O, and Lefkowitz RJ (2006) Beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J Biol Chem 281:1261-1273.
30. Shimpukade B, Hudson BD, Hovgaard CK, Milligan G, and Ulven T (2012) Discovery of a potent and selective GPR120 agonist. J Med Chem 55:4511-4515.
31. Smith NJ, Stoddart LA, Devine NM, Jenkins L, and Milligan G (2009) The action and mode of binding of thiazolidinedione ligands at free fatty acid receptor 1. J Biol Chem 284:17527-17539.
32. Stoddart LA, Smith NJ, and Milligan G (2008a) International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol Rev 60:405-417.
33. Stoddart LA, Smith NJ, Jenkins L, Brown AJ, and Milligan G (2008b) Conserved polar residues in transmembrane domains V, VI, and VII of free fatty acid receptor 2 and free fatty acid receptor 3 are required for the binding and function of short chain fatty acids. J Biol Chem 283:32913-32924.
34. Sun Q, Hirasawa A, Hara T, Kimura I, Adachi T, Awaji T, Ishiguro M, Suzuki T, Miyata N, and Tsujimoto G (2010) Structure-activity relationships of GPR120 agonists based on a docking simulation. Mol Pharmacol 78:804-810.
35. Suzuki T, Igari S-I, Hirasawa A, Hata M, Ishiguro M, Fujieda H, Itoh Y, Hirano T, Nakagawa H, and Ogura M et al. (2008) Identification of G protein-coupled receptor 120-selective agonists derived from PPARy agonists. J Med Chem 51:7640-7644.
36. Taneera J, Lang S, Sharma A, Fadista J, Zhou Y, Ahlqvist E, Jonsson A, Lyssenko V, Vikman P, and Hansson O et al. (2012) A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metab 16:122-134.
37. Takasaki J, Saito T, Taniguchi M, Kawasaki T, Moritani Y, Hayashi K, and Kobori M (2004) A novel Gaq/11-selective inhibitor. J Biol Chem 279:47438-47445.
38. Tikhonova IG, Sum CS, Neumann S, Thomas CJ, Raaka BM, Costanzi S, and Gershengorn MC (2007) Bidirectional, iterative approach to the structural delineation of the functional "chemoprint" in GPR40 for agonist recognition. J Med Chem 50:2981-2989. (Pubitemid 47001241)
39. Ulven T (2012) Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne) 3:111.
40. Wang J, Wu X, Simonavicius N, Tian H, and Ling L (2006) Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem 281:34457-34464. (Pubitemid 46036653)
41. Watson S-J, Brown A J H, and Holliday ND (2012) Differential signaling by splice variants of the human free fatty acid receptor GPR120. Mol Pharmacol 81:631-642.