Seven Transmembrane-spanning Receptors for Free Fatty Acids as Therapeutic Targets for Diabetes Mellitus: Pharmacological, Phylogenetic, and Drug Discovery Aspects (2008)

Free fatty acids (FFAs) 2The abbreviations used are: FFAs, free fatty acids; 7TMRs, seven transmembrane-spanning receptors; FFARs, FFA receptors; TMs, transmembrane domains. take part in many physiological processes in different tissues such as skeletal muscle, liver, heart, and pancreas by providing an oxidative energy source. In addition, FFAs are potent signaling molecules (1Coppack S.W. Jensen M.D. Miles J.M. J. Lipid Res. 1994; 35: 177-193Abstract Full Text PDF PubMed Google Scholar). Dysregulation of FFA metabolism is responsible for insulin resistance and type 2 diabetes mellitus (2Wilding J.P. Diabetic Med. 2007; 24: 934-945Crossref PubMed Scopus (158) Google Scholar). The presence of some FFAs is essential for glucose-stimulated insulin secretion from pancreatic β-cells. However, if FFAs are chronically in excess, they can reduce insulin biosynthesis and secretion and induce β-cell apoptosis (2Wilding J.P. Diabetic Med. 2007; 24: 934-945Crossref PubMed Scopus (158) Google Scholar). The regulatory effect of FFAs occurs in part by their involvement as substrates in intracellular lipid signaling pathways; however, FFAs also signal directly via seven transmembrane-spanning receptors (7TMRs; G protein-coupled receptors). Here, we consider 7TMRs that are activated by FFAs and FFA amides. Furthermore, we describe the identification and characterization of small molecule ligands for these FFA receptors (FFARs) that may be useful for treating patients with diabetes mellitus. All members of a previously characterized cluster of orphan 7TMRs comprising FFAR1 (previously known as GPR40), FFAR2 (previously known as GPR43), and FFAR3 (previously known as GPR41) are activated by FFAs within physiological concentration ranges (3Brown A.J. Jupe S. Briscoe C.P. DNA Cell Biol. 2005; 24: 54-61Crossref PubMed Scopus (120) Google Scholar). More recently, the orphan receptors GPR119 and GPR120 were identified as targets of FFAs and FFA amides, respectively (4Overton H.A. Babbs A.J. Doel S.M. Fyfe M.C. Gardner L.S. Griffin G. Jackson H.C. Procter M.J. Rasamison C.M. Tang-Christensen M. Widdowson P.S. Williams G.M. Reynet C. Cell Metab. 2006; 3: 167-175Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 5Hirasawa A. Tsumaya K. Awaji T. Katsuma S. Adachi T. Yamada M. Sugimoto Y. Miyazaki S. Tsujimoto G. Nat. Med. 2005; 11: 90-94Crossref PubMed Scopus (1191) Google Scholar). The FFAR1 cluster is tandemly located on chromosome 19q13.1. These receptors share a relatively high sequence similarity but have diverse tissue distribution. FFAR1 and GPR120 are activated by medium- to long-chain fatty acids, whereas FFAR2 and FFAR3 are activated by short-chain fatty acids. GPR119 is activated by long-chain FFA amides such as oleoylethanolamide and lysophosphatidylcholine (6Rayasam G.V. Tulasi V.K. Davis J.A. Bansal V.S. Expert Opin. Ther. Targets. 2007; 11: 661-671Crossref PubMed Scopus (94) Google Scholar, 7Winzell M.S. Ahren B. Pharmacol. Ther. 2007; 116: 437-448Crossref PubMed Scopus (158) Google Scholar). FFAR1 couples preferentially to Gq to stimulate the activity of phospholipase C (8Briscoe C.P. Tadayyon M. Andrews J.L. Benson W.G. Chambers J.K. Eilert M.M. Ellis C. Elshourbagy N.A. Goetz A.S. Minnick D.T. Murdock P.R. Sauls H.R. Shabon U. Spinage L.D. Strum J.C. Szekeres P.G. Tan K.B. Way J.M. Ignar D.M. Wilson S. Muir A.I. J. Biol. Chem. 2003; 278: 11303-11311Abstract Full Text Full Text PDF PubMed Scopus (917) Google Scholar, 9Itoh Y. Kawamata Y. Harada M. Kobayashi M. Fujii R. Fukusumi S. Ogi K. Hosoya M. Tanaka Y. Uejima H. Tanaka H. Maruyama M. Satoh R. Okubo S. Kizawa H. Komatsu H. Matsumura F. Noguchi Y. Shinohara T. Hinuma S. Fujisawa Y. Fujino M. Nature. 2003; 422: 173-176Crossref PubMed Scopus (1282) Google Scholar). FFAR3 appears to be selective for Gi activation, whereas FFAR2 can activate Gi and Gq (3Brown A.J. Jupe S. Briscoe C.P. DNA Cell Biol. 2005; 24: 54-61Crossref PubMed Scopus (120) Google Scholar). GPR119 isaGs-coupled receptor (10Soga T. Ohishi T. Matsui T. Saito T. Matsumoto M. Takasaki J. Matsumoto S. Kamohara M. Hiyama H. Yoshida S. Momose K. Ueda Y. Matsushime H. Kobori M. Furuichi K. Biochem. Biophys. Res. Commun. 2005; 326: 744-751Crossref PubMed Scopus (298) Google Scholar). The ability of FFAs to elevate Ca2+ in mouse intestinal endocrine STC-1 cells via GPR120 indicates interaction with members of the Gq family (11Milligan G. Stoddart L.A. Brown A.J. Cell. Signal. 2006; 18: 1360-1365Crossref PubMed Scopus (63) Google Scholar). FFAR1 is highly expressed in the insulin-secreting β-cells of the pancreas (8Briscoe C.P. Tadayyon M. Andrews J.L. Benson W.G. Chambers J.K. Eilert M.M. Ellis C. Elshourbagy N.A. Goetz A.S. Minnick D.T. Murdock P.R. Sauls H.R. Shabon U. Spinage L.D. Strum J.C. Szekeres P.G. Tan K.B. Way J.M. Ignar D.M. Wilson S. Muir A.I. J. Biol. Chem. 2003; 278: 11303-11311Abstract Full Text Full Text PDF PubMed Scopus (917) Google Scholar) and is present at lower levels in pancreatic α-cells also (12Flodgren E. Olde B. Meidute-Abaraviciene S. Winzell M.S. Ahren B. Salehi A. Biochem. Biophys. Res. Commun. 2007; 354: 240-245Crossref PubMed Scopus (92) Google Scholar). GPR119 is significantly enriched in human pancreatic and gastrointestinal tissue (13Chu Z.-L. Carroll C. Alfonso J. Gutierrez V. He H. Lucman A. Pedraza M. Mondala H. Gao H. Bagnol D. Chen R. Jones R.M. Behan D.P. Leonard J. Endocrinology. 2008; 10.1210/en.2007-0966Google Scholar); it is expressed mainly in β-cells of isolated pancreatic islets from mice (14Overton H.A. Fyfe M.C.T. Reynet C. Br. J. Pharmacol. 2008; 153: S76-S81Crossref PubMed Scopus (216) Google Scholar). GPR120 is abundantly expressed in the intestine but is not expressed in the pancreas or clonal β-cells (5Hirasawa A. Tsumaya K. Awaji T. Katsuma S. Adachi T. Yamada M. Sugimoto Y. Miyazaki S. Tsujimoto G. Nat. Med. 2005; 11: 90-94Crossref PubMed Scopus (1191) Google Scholar). FFAR2 and FFAR3 have different tissue distributions and more broad expression profiles; FFAR2 is abundant in leukocytes and adipose tissue (6Rayasam G.V. Tulasi V.K. Davis J.A. Bansal V.S. Expert Opin. Ther. Targets. 2007; 11: 661-671Crossref PubMed Scopus (94) Google Scholar), whereas FFAR3 is highly expressed in brain, lung, and adipose tissue. 7TMRs form a large transmembrane protein superfamily that encompasses >1000 unique members in the human genome. They are composed of a single polypeptide chain that crosses the plasma membrane seven times via α-helical transmembrane domains (TMs). The N-terminal ends of these receptors are located extracellularly, whereas their C-terminal ends are in the cytoplasm. Phylogenetic analyses show that 7TMRs are clustered into five families: glutamate, rhodopsin, adhesion, Frizzled/Taste2, and secretin (15Fredriksson R. Lagerstrom M.C. Lundin L.G. Schioth H.B. Mol. Pharmacol. 2003; 63: 1256-1272Crossref PubMed Scopus (2257) Google Scholar). The four human 7TMRs for FFAs and the single human receptor for FFA amides (6Rayasam G.V. Tulasi V.K. Davis J.A. Bansal V.S. Expert Opin. Ther. Targets. 2007; 11: 661-671Crossref PubMed Scopus (94) Google Scholar, 16Fyfe M. White J. Widdowson P. Overton H. Reynet C. Diabetes. 2007; 56: A142Google Scholar) belong to the rhodopsin family, a tree representation of which is provided in Fig. 1. According to sequence similarity, FFAR1, FFAR2, and FFAR3 form a well defined receptor cluster (the FFAR1 cluster) that belongs to the subfamily of nucleotide and lipid receptors (17Tikhonova I.G. Sum C.S. Neumann S. Thomas C.J. Raaka B.M. Costanzi S. Gershengorn M.C. J. Med. Chem. 2007; 50: 2981-2989Crossref PubMed Scopus (86) Google Scholar). The TMs of the three receptors share ∼39% sequence identity. FFAR1 is the most dissimilar receptor of the cluster, sharing ∼35% TM sequence identity with other members. As mentioned above, FFAR1 is the only receptor in the cluster to be selective for medium- to long-chain fatty acids, whereas FFAR2 and FFAR3 are activated by short-chain fatty acids. Receptors of the nucleotide and lipid subfamily are typically activated by negatively charged ligands and are characterized by the presence of basic residues at specific positions within their TMs. A chemogenomic analysis of 7TMRs, conducted comparing 30 residues within the putative common binding cavity located in the TM bundle of the receptors, suggested the involvement of two conserved Arg residues at positions 5.39 and 7.35 in the coordination of the negative charges of FFAs by the receptors belonging to the FFAR1 cluster (18Surgand J.S. Rodrigo J. Kellenberger E. Rognan D. Proteins. 2006; 62: 509-538Crossref PubMed Scopus (212) Google Scholar). 3TM positions are identified with the indexing scheme of Ballesteros and Weinstein (19Ballesteros J.A. Weinstein H. Methods Neurosci. 1995; 25: 366-428Crossref Scopus (2576) Google Scholar). This analysis also proposed the difference in bulkiness of the residue at position 6.48, located deeply in the binding cavity, as an explanation for the selectivity of long- versus short-chain fatty acids. Site-directed mutagenesis experiments, guided by molecular modeling, did not confirm the latter hypothesis but did confirm the proposed role of the conserved Arg residues (17Tikhonova I.G. Sum C.S. Neumann S. Thomas C.J. Raaka B.M. Costanzi S. Gershengorn M.C. J. Med. Chem. 2007; 50: 2981-2989Crossref PubMed Scopus (86) Google Scholar). The medium- to long-chain FFAR GPR120 does not belong to the FFAR1 cluster. Although evolutionarily conserved, GPR120 lacks close relatives (20Fredriksson R. Hoglund P.J. Gloriam D.E.I. Lagerstrom M.C. Schioth H.B. FEBS Lett. 2003; 554: 381-388Crossref PubMed Scopus (232) Google Scholar) and belongs to a subfamily that includes several orphan receptors and a cluster of melatonin receptors. Although GPR120 and FFAR1 are both activated by long-chain FFAs, the two receptors exhibit only 19% sequence identity. Moreover, our models predict that they do not share ligand recognition determinants: none of the FFAR1 residues proposed to be involved in ligand binding are conserved in GPR120, and this receptor does not have basic residues in the TM cavity. As mentioned above, long-chain FFA amides such as oleoylethanolamide have been identified as the endogenous ligands of GPR119. This receptor is also activated by phospholipids and belongs to the subfamily of the biogenic amine and MECA (melanocortin, endothelial, cannabinoid, and adenosine) receptors, a tree representation of which is provided elsewhere (21Costanzi S. Ivanov A.A. Tikhonova I.G. Jacobson K.A. Caldwell G.W. Rahman A.U. Player M.R. Chouday M.I. Frontiers in Drug Design and Discovery. 3. Bentham Science Publishers Ltd., Oak Park, IL2007: 63-79Google Scholar). GPR119 does not show significant similarity to the known receptors for FFAs, sharing only 24 and 18% TM sequence identity with GPR120 and FFAR1, respectively. The different clustering of FFAR1 and GPR119 based on sequence comparison is in line with the differences in their ligand selectivity: FFAR1 and relatives are activated by FFAs and cluster with receptors typically activated by negatively charged ligands such as nucleotide and dicarboxylic acids, whereas GPR119 is activated by FFA amides and clusters with receptors typically for neutral ligands such as nucleosides. The closest homologs of GPR119 are the adenosine A1 and A3 receptors, with which it shares 28% TM sequence identity. Molecular determinants for the recognition of linoleate and GW9508 (a synthetic agonist) (22Garrido D.M. Corbett D.F. Dwornik K.A. Goetz A.S. Littleton T.R. McKeown S.C. Mills W.Y. Smalley T.L. Briscoe C.P. Peat A.J. Bioorg. Med. Chem. Lett. 2006; 16: 1840-1845Crossref PubMed Scopus (99) Google Scholar, 23Briscoe C.P. Peat A.J. McKeown S.C. Corbett D.F. Goetz A.S. Littleton T.R. Mccoy D.C. Kenakin T.P. Andrews J.L. Ammala C. Fornwald J.A. Ignar D.M. Jenkinson S. Br. J. Pharmacol. 2006; 148: 619-628Crossref PubMed Scopus (358) Google Scholar) by FFAR1 were proposed on the basis of sequence comparisons, rhodopsin-based homology modeling, and mutagenesis (17Tikhonova I.G. Sum C.S. Neumann S. Thomas C.J. Raaka B.M. Costanzi S. Gershengorn M.C. J. Med. Chem. 2007; 50: 2981-2989Crossref PubMed Scopus (86) Google Scholar, 24Sum C.S. Tikhonova I.G. Neumann S. Engel S. Raaka B.M. Costanzi S. Gershengorn M.C. J. Biol. Chem. 2007; 282: 29248-29255Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Our experimentally supported model suggests that ligands bind within the upper part of the helical bundle between TM3, TM4, TM5, and TM6. For both linoleate and GW9508, the negatively charged headgroups are oriented toward the extracellular opening of the cavity, whereas the hydrophobic tails, in semi-folded conformation, are oriented toward the center of the receptor. In particular, the carboxylate groups of these ligands are coordinated by three residues: Arg-183(5.39) and Arg-258(7.35), both conserved through the FFAR1 cluster, and Asn-244(6.55). Mutation of these residues markedly impairs activation of FFAR1 by linoleate or GW9508. A potential involvement of the Arg residues was predicted previously by the chemogenomic analysis mentioned above (18Surgand J.S. Rodrigo J. Kellenberger E. Rognan D. Proteins. 2006; 62: 509-538Crossref PubMed Scopus (212) Google Scholar). Residues located at position 6.55 have been shown to be important components of ligand recognition in several members of the nucleotide and lipid subfamily, including the nucleotide P2Y1-like receptors that have a basic residue involved in coordination of ligand phosphates at this site (25Costanzi S. Gao Jacobson K.A. J. Med. Chem. PubMed Scopus Google Scholar). Our model also suggests that the hydrophobic of the ligands in a by and hydrophobic residues that to more significantly with GW9508 with In particular, two and are predicted to with GW9508 in a on their is that residues at position are at the center of the putative common binding of 7TMRs and in ligand recognition in a of receptors, including the receptors that at this site an residue involved in coordination of the ligand In were with diabetes and of these were as type 2 The of this is and is to is a of type 2 diabetes which is by insulin secretion and secretion of 2007; PubMed Scopus Google Scholar). important for of this is to stimulate insulin secretion and to reduce The of the of and their in suggested that these receptors be targets for synthetic (6Rayasam G.V. Tulasi V.K. Davis J.A. Bansal V.S. Expert Opin. Ther. Targets. 2007; 11: 661-671Crossref PubMed Scopus (94) Google Scholar, V. Endocrinology. 2007; 148: PubMed Scopus Google Scholar). 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Cell Metab. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of FFAR1 in high or in may be a to type 2 diabetes P. R. M.D. H. Cell Metab. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Although it FFAR1 a role in metabolism activation by FFAs, mice may be from high and P. R. M.D. H. Cell Metab. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, but T. E. C. T.L. J. D.C. V. Diabetes. 2007; 56: PubMed Scopus Google Scholar). these that FFAR1 ligands be useful for insulin secretion in patients with type 2 diabetes mellitus or for negative of of this FFAR1 been a of in the (22Garrido D.M. Corbett D.F. Dwornik K.A. Goetz A.S. Littleton T.R. McKeown S.C. Mills W.Y. Smalley T.L. Briscoe C.P. Peat A.J. Bioorg. Med. Chem. Lett. 2006; 16: 1840-1845Crossref PubMed Scopus (99) Google Scholar, 23Briscoe C.P. Peat A.J. McKeown S.C. Corbett D.F. Goetz A.S. Littleton T.R. Mccoy D.C. Kenakin T.P. Andrews J.L. Ammala C. Fornwald J.A. Ignar D.M. Jenkinson S. Br. J. Pharmacol. 2006; 148: 619-628Crossref PubMed Scopus (358) Google Scholar, J. P. J. Y. C. J. J. Med. Chem. 2007; 50: PubMed Scopus Google Scholar, S.C. Corbett D.F. Goetz A.S. Littleton T.R. E. Briscoe C.P. Peat A.J. Bioorg. Med. Chem. Lett. 2007; PubMed Scopus Google Scholar, J. A. R. Y. M. M. Y. J. J. J. J. J. G. J. J. Chen M. E. K. H. S. D. The D. Scholar). GPR119 of expression in the pancreas and on and (14Overton H.A. Fyfe M.C.T. Reynet C. Br. J. Pharmacol. 2008; 153: S76-S81Crossref PubMed Scopus (216) Google Scholar). A selective for in and and adipose tissue (4Overton H.A. Babbs A.J. Doel S.M. Fyfe M.C. Gardner L.S. Griffin G. Jackson H.C. Procter M.J. Rasamison C.M. Tang-Christensen M. Widdowson P.S. Williams G.M. Reynet C. Cell Metab. 2006; 3: 167-175Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar). GPR119 directly on pancreatic β-cells to insulin and to in mice but not in mice Z.-L. Jones R.M. He H. Carroll C. Gutierrez V. Lucman A. M. Gao H. Mondala H. Bagnol D. D. Y. K. G. Behan D.P. Leonard J. Endocrinology. 2007; 148: PubMed Scopus Google Scholar). The intestinal polypeptide and in by insulin and β-cell Med. 2006; PubMed Scopus Google Scholar, 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). The receptor (a belonging to the secretin family that is expressed in pancreatic to be a for identification of small molecule ligands (11Milligan G. Stoddart L.A. Brown A.J. Cell. Signal. 2006; 18: 1360-1365Crossref PubMed Scopus (63) Google Scholar). of secretion from intestinal endocrine (13Chu Z.-L. Carroll C. Alfonso J. Gutierrez V. He H. Lucman A. Pedraza M. Mondala H. Gao H. Bagnol D. Chen R. Jones R.M. Behan D.P. Leonard J. Endocrinology. 2008; 10.1210/en.2007-0966Google Scholar) that and GPR119 may by this GPR120, which is not expressed in is involved in of M.S. Ahren B. Pharmacol. Ther. 2007; 116: 437-448Crossref PubMed Scopus (158) Google Scholar) FFA activation of GPR120 on intestinal endocrine cells of also (5Hirasawa A. Tsumaya K. Awaji T. Katsuma S. Adachi T. Yamada M. Sugimoto Y. Miyazaki S. Tsujimoto G. Nat. Med. 2005; 11: 90-94Crossref PubMed Scopus (1191) Google Scholar). As GPR120 levels and as an effect on and of GPR120 be for of diabetes and (6Rayasam G.V. Tulasi V.K. Davis J.A. Bansal V.S. Expert Opin. Ther. Targets. 2007; 11: 661-671Crossref PubMed Scopus (94) Google Scholar). Drug to have on for which the of selective been by and (4Overton H.A. Babbs A.J. Doel S.M. Fyfe M.C. Gardner L.S. Griffin G. Jackson H.C. Procter M.J. Rasamison C.M. Tang-Christensen M. Widdowson P.S. Williams G.M. Reynet C. Cell Metab. 2006; 3: 167-175Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, Z.-L. Jones R.M. He H. Carroll C. Gutierrez V. Lucman A. M. Gao H. Mondala H. Bagnol D. D. Y. K. G. Behan D.P. Leonard J. Endocrinology. 2007; 148: PubMed Scopus Google Scholar), and on FFAR1 (22Garrido D.M. Corbett D.F. Dwornik K.A. Goetz A.S. Littleton T.R. McKeown S.C. Mills W.Y. Smalley T.L. Briscoe C.P. Peat A.J. Bioorg. Med. Chem. Lett. 2006; 16: 1840-1845Crossref PubMed Scopus (99) Google Scholar, 23Briscoe C.P. Peat A.J. McKeown S.C. Corbett D.F. Goetz A.S. Littleton T.R. Mccoy D.C. Kenakin T.P. Andrews J.L. Ammala C. Fornwald J.A. Ignar D.M. Jenkinson S. Br. J. Pharmacol. 2006; 148: 619-628Crossref PubMed Scopus (358) Google Scholar, J. P. J. Y. C. J. J. Med. Chem. 2007; 50: PubMed Scopus Google Scholar, S.C. Corbett D.F. Goetz A.S. Littleton T.R. E. Briscoe C.P. Peat A.J. Bioorg. Med. Chem. Lett. 2007; PubMed Scopus Google Scholar, J. A. R. Y. M. M. Y. J. J. J. J. J. G. J. J. Chen M. E. K. H. S. D. The D. Scholar). of GPR119 and FFAR1 have also been the of the of a of FFAR1 with the receptor The is not to endogenous which in both are medium- to long-chain FFAs, but also includes synthetic such as the which FFAR1 with K. E. C. Olde B. Biochem. Biophys. Res. Commun. 2003; PubMed Scopus Google Scholar). The for selective FFAR1 ligands a of high by through or The of the GW9508 was identified by as a potent FFAR1 with an of whereas FFAs exhibit in the (22Garrido D.M. Corbett D.F. Dwornik K.A. Goetz A.S. Littleton T.R. McKeown S.C. Mills W.Y. Smalley T.L. Briscoe C.P. Peat A.J. Bioorg. Med. Chem. Lett. 2006; 16: 1840-1845Crossref PubMed Scopus (99) Google Scholar, 23Briscoe C.P. Peat A.J. McKeown S.C. Corbett D.F. Goetz A.S. Littleton T.R. Mccoy D.C. Kenakin T.P. Andrews J.L. Ammala C. Fornwald J.A. Ignar D.M. Jenkinson S. Br. J. Pharmacol. 2006; 148: 619-628Crossref PubMed Scopus (358) Google Scholar, S.C. Corbett D.F. Goetz A.S. Littleton T.R. E. Briscoe C.P. Peat A.J. Bioorg. Med. Chem. Lett. 2007; PubMed Scopus Google Scholar). This significant selectivity receptors, for which it in the and does not activate other members of the FFAR1 cluster. However, it GPR120 with which is with the of long-chain A selective FFAR1 was identified the GW9508 a free and a whereas the an and a According to our these differences may be responsible for the of The of a negatively charged in the may the of the of the residues at positions and 7.35 that occurs in the of Moreover, the of the may the ligand from with residues located in the of the binding cavity that may be an important of the activation through of a of a that from high identified a of as of FFAR1 with and J. P. J. Y. C. J. J. Med. Chem. 2007; 50: PubMed Scopus Google Scholar). Moreover, a of acids have been identified by at J. A. R. Y. M. M. Y. J. J. J. J. J. G. J. J. Chen M. E. K. H. S. D. The D. Scholar). have used our model of FFAR1 in a to ligands for the receptor I.G. Sum C.S. Neumann S. Engel S. Raaka B.M. Costanzi S. Gershengorn M.C. J. Med. Chem. 2008; PubMed Scopus Google Scholar). This used the of known FFAR1 ligands in with the model of the binding to a diverse of in high a large of was on the basis of similarity to GW9508 and to a the groups of the of the two and high molecular on the FFAR1 This to the identification of diverse FFAR1 ligands three and of molecules a of and were identified by for close of the All of the the and of the most potent and the most potent are shown in Fig. As with GW9508, the two are characterized by an carboxylate coordinated by and the two are characterized by the of the carboxylate with a that this may be responsible for their with type 2 diabetes mellitus a of β-cell and 2007; PubMed Scopus Google Scholar). β-cell and β-cell to be at of the the for of β-cell not been 2007; PubMed Scopus Google Scholar). the ability to β-cell in patients at for type or 2 diabetes significant for for β-cells in are is that the highly selective expression of FFAR1 on the of β-cells present a for a high high ligands also be for of a for of binding to FFAR1 in in that of for this receptor. ligands for be for these in to to patients with diabetes mellitus and ligands to the of G. Tikhonova and Sum for in our of FFAR1 and for providing the in Fig.