[en] The orphan G protein-coupled receptor GPR27 appears to play a role in insulin production, secretion, lipid metabolism, neuronal plasticity, and l-lactate homeostasis. However, investigations on the function of GPR27 are impaired by the lack of potent and efficacious agonists. We describe herein the development of di- and trisubstituted benzamide derivatives 4a-e, 7a-z, and 7aa-ai, which display GPR27-specific activity in a β-arrestin 2 recruitment-based assay. Highlighted compounds are PT-91 (7p: pEC50 6.15; Emax 100%) and 7ab (pEC50 6.56; Emax 99%). A putative binding mode was revealed by the docking studies of 7p and 7ab with a GPR27 homology model. The novel active compounds exhibited no GPR27-mediated activation of G proteins, indicating that the receptor may possess an atypical profile. Compound 7p displays high metabolic stability and brain exposure in mice. Thus, 7p represents a novel tool to investigate the elusive pharmacology of GPR27 and assess its potential as a drug target.
Pillaiyar, Thanigaimalai ; Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Wozniak, Monika ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Abboud, Dayana ; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Molecular Pharmacology
Rasch, Alexander; Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Liebing, Aenne-Dorothea; Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany
Poso, Antti ; Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany ; Cluster of Excellence iFIT (EXC 2180) "Image-Guided & Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany ; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland
Kronenberger, Thales; Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany ; Cluster of Excellence iFIT (EXC 2180) "Image-Guided & Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany ; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland
Stäubert, Claudia; Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany
Laufer, Stefan A ; Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany ; Cluster of Excellence iFIT (EXC 2180) "Image-Guided & Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany
Hanson, Julien ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Language :
English
Title :
Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency.
BMBF - Bundesministerium für Bildung und Forschung DFG - Deutsche Forschungsgemeinschaft MWK - Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg F.R.S.-FNRS - Fonds de la Recherche Scientifique Universität Leipzig
Funding text :
TüCAD2 is funded by the Federal Ministry of Education and Research (BMBF) and the Baden-Württemberg Ministry of Science as part of the Excellence Strategy of the German Federal and State Governments. T.K. was supported by the Fortüne initiative (no. 2613-0-0) and by the iFIT, which are both initiatives from the Excellence Strategy of the German Federal and State Governments. The authors would like to thank the CSC-Finland for the generous computational resources. C.S. and A.-D.L. are supported by the Deutsche Forschungsgemeinschaft-Project-ID 407707190, the SFB1423 and the Pre-Doc Award of Leipzig University. The authors thank Petra Krumbholz for technical assistance. J. Hanson is a F.R.S.-FNRS senior research associate and was supported by a research project grant from the F.R.S.-FNRS (PDRT.0111.19). The authors thank Kristine Schmidt for proofreading (language).
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Bibliography
Alexander, S. P.; Christopoulos, A.; Davenport, A. P.; Kelly, E.; Mathie, A.; Peters, J. A.; Veale, E. L.; Armstrong, J. F.; Faccenda, E.; Harding, S. D.; Pawson, A. J.; Southan, C.; Davies, J. A.; Abbracchio, M. P.; Alexander, W.; Al-Hosaini, K.; Bäck, M.; Barnes, N. M.; Bathgate, R.; Beaulieu, J.-M.; Bernstein, K. E.; Bettler, B.; Birdsall, N. J. M.; Blaho, V.; Boulay, F.; Bousquet, C.; Bräuner-Osborne, H.; Burnstock, G.; Caló, G.; Castaño, J. P.; Catt, K. J.; Ceruti, S.; Chazot, P.; Chiang, N.; Chini, B.; Chun, J.; Cianciulli, A.; Civelli, O.; Clapp, L. H.; Couture, R.; Csaba, Z.; Dahlgren, C.; Dent, G.; Singh, K. D.; Douglas, S. D.; Dournaud, P.; Eguchi, S.; Escher, E.; Filardo, E. J.; Fong, T.; Fumagalli, M.; Gainetdinov, R. R.; Gasparo, M. d.; Gerard, C.; Gershengorn, M.; Gobeil, F.; Goodfriend, T. L.; Goudet, C.; Gregory, K. J.; Gundlach, A. L.; Hamann, J.; Hanson, J.; Hauger, R. L.; Hay, D. L.; Heinemann, A.; Hollenberg, M. D.; Holliday, N. D.; Horiuchi, M.; Hoyer, D.; Hunyady, L.; Husain, A.; Ijzerman, A. P.; Inagami, T.; Jacobson, K. A.; Jensen, R. T.; Jockers, R.; Jonnalagadda, D.; Karnik, S.; Kaupmann, K.; Kemp, J.; Kennedy, C.; Kihara, Y.; Kitazawa, T.; Kozielewicz, P.; Kreienkamp, H.-J.; Kukkonen, J. P.; Langenhan, T.; Leach, K.; Lecca, D.; Lee, J. D.; Leeman, S. E.; Leprince, J.; Li, X. X.; Williams, T. L.; Lolait, S. J.; Lupp, A.; Macrae, R.; Maguire, J.; Mazella, J.; McArdle, C. A.; Melmed, S.; Michel, M. C.; Miller, L. J.; Mitolo, V.; Mouillac, B.; Müller, C. E.; Murphy, P.; Nahon, J.-L.; Ngo, T.; Norel, X.; Nyimanu, D.; O’Carroll, A.-M.; Offermanns, S.; Panaro, M. A.; Parmentier, M.; Pertwee, R. G.; Pin, J.-P.; Prossnitz, E. R.; Quinn, M.; Ramachandran, R.; Ray, M.; Reinscheid, R. K.; Rondard, P.; Rovati, G. E.; Ruzza, C.; Sanger, G. J.; Schöneberg, T.; Schulte, G.; Schulz, S.; Segaloff, D. L.; Serhan, C. N.; Stoddart, L. A.; Sugimoto, Y.; Summers, R.; Tan, V. P.; Thal, D.; Thomas, W. W.; Timmermans, P. B. M. W. M.; Tirupula, K.; Tulipano, G.; Unal, H.; Unger, T.; Valant, C.; Vanderheyden, P.; Vaudry, D.; Vaudry, H.; Vilardaga, J.-P.; Walker, C. S.; Wang, J. M.; Ward, D. T.; Wester, H.-J.; Willars, G. B.; Woodruff, T. M.; Yao, C.; Ye, R. D. THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G Protein-Coupled Receptors. Br. J. Pharmacol. 2021, 178, S27- S156, 10.1111/bph.15538
Hauser, A. S.; Attwood, M. M.; Rask-Andersen, M.; Schiöth, H. B.; Gloriam, D. E. Trends in GPCR Drug Discovery: New Agents, Targets and Indications. Nat. Rev. Drug Discov. 2017, 16 ( 12), 829- 842, 10.1038/nrd.2017.178
Sriram, K.; Insel, P. A. G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?. Mol. Pharmacol. 2018, 93 ( 4), 251- 258, 10.1124/mol.117.111062
Laschet, C.; Dupuis, N.; Hanson, J. The G Protein-Coupled Receptors Deorphanization Landscape. Biochem. Pharmacol. 2018, 153, 62- 74, 10.1016/j.bcp.2018.02.016
Davenport, A. P.; Alexander, S. P. H.; Sharman, J. L.; Pawson, A. J.; Benson, H. E.; Monaghan, A. E.; Liew, W. C.; Mpamhanga, C. P.; Bonner, T. I.; Neubig, R. R.; Pin, J. P.; Spedding, M.; Harmar, A. J. International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands. Pharmacol. Rev. 2013, 65 ( 3), 967- 986, 10.1124/pr.112.007179
Roth, B. L.; Kroeze, W. K. Integrated Approaches for Genome-Wide Interrogation of the Druggable Non-Olfactory G Protein-Coupled Receptor Superfamily. J. Biol. Chem. 2015, 290 ( 32), 19471- 19477, 10.1074/jbc.R115.654764
Edwards, A. M.; Isserlin, R.; Bader, G. D.; Frye, S. V.; Willson, T. M.; Yu, F. H. Too Many Roads Not Taken. Nature 2011, 470 ( 7333), 163- 165, 10.1038/470163a
Stäubert, C.; Wozniak, M.; Dupuis, N.; Laschet, C.; Pillaiyar, T.; Hanson, J. Superconserved Receptors Expressed in the Brain: Expression, Function, Motifs and Evolution of an Orphan Receptor Family. Pharmacol. Ther. 2022, 240, 108217, 10.1016/j.pharmthera.2022.108217
Bayrak, A.; Hanson, J.; Laufer, S.; Pillaiyar, T. Super-Conserved Receptors Expressed in the Brain: Biology and Medicinal Chemistry Efforts. Future Med. Chem. 2022, 14 ( 12), 899- 913, 10.4155/fmc-2022-0006
Matsumoto, M.; Saito, T.; Takasaki, J.; Kamohara, M.; Sugimoto, T.; Kobayashi, M.; Tadokoro, M.; Matsumoto, S.; Ohishi, T.; Furuichi, K. An Evolutionarily Conserved G-Protein Coupled Receptor Family, SREB, Expressed in the Central Nervous System. Biochem. Biophys. Res. Commun. 2000, 272 ( 2), 576- 582, 10.1006/bbrc.2000.2829
Regard, J. B.; Sato, I. T.; Coughlin, S. R. Anatomical Profiling of G Protein-Coupled Receptor Expression. Cell 2008, 135 ( 3), 561- 571, 10.1016/j.cell.2008.08.040
Ku, G. M.; Pappalardo, Z.; Luo, C. C.; German, M. S.; McManus, M. T. An siRNA Screen in Pancreatic Beta Cells Reveals a Role for Gpr27 in Insulin Production. PLoS Genet. 2012, 8 ( 1), e1002449 10.1371/journal.pgen.1002449
Chopra, D. G.; Yiv, N.; Hennings, T. G.; Zhang, Y.; Ku, G. M. Deletion of Gpr27 in Vivo Reduces Insulin mRNA but Does Not Result in Diabetes. Sci. Rep. 2020, 10 ( 1), 5629, 10.1038/s41598-020-62358-4
Breton, T. S.; Sampson, W. G. B.; Clifford, B.; Phaneuf, A. M.; Smidt, I.; True, T.; Wilcox, A. R.; Lipscomb, T.; Murray, C.; DiMaggio, M. A. Characterization of the G Protein-Coupled Receptor Family SREB across Fish Evolution. Sci. Rep. 2021, 11 ( 1), 12066, 10.1038/s41598-021-91590-9
Nath, A. K.; Ma, J.; Chen, Z.-Z.; Li, Z.; Vitery, M. D. C.; Kelley, M. L.; Peterson, R. T.; Gerszten, R. E.; Yeh, J.-R. J. Genetic Deletion of Gpr27 Alters Acylcarnitine Metabolism, Insulin Sensitivity, and Glucose Homeostasis in Zebrafish. FASEB J. 2020, 34 ( 1), 1546- 1557, 10.1096/fj.201901466R
Dolanc, D.; Zorec, T. M.; Smole, Z.; Maver, A.; Horvat, A.; Pillaiyar, T.; Trkov Bobnar, S.; Vardjan, N.; Kreft, M.; Chowdhury, H. H.; Zorec, R. The Activation of GPR27 Increases Cytosolic L-Lactate in 3T3 Embryonic Cells and Astrocytes. Cells 2022, 11 ( 6), 1009, 10.3390/cells11061009
Dupuis, N.; Laschet, C.; Franssen, D.; Szpakowska, M.; Gilissen, J.; Geubelle, P.; Soni, A.; Parent, A.-S.; Pirotte, B.; Chevigné, A.; Twizere, J.-C.; Hanson, J. Activation of the Orphan G Protein-Coupled Receptor GPR27 by Surrogate Ligands Promotes β-Arrestin 2 Recruitment. Mol. Pharmacol. 2017, 91 ( 6), 595- 608, 10.1124/mol.116.107714
Pillaiyar, T.; Rosato, F.; Wozniak, M.; Blavier, J.; Charles, M.; Laschet, C.; Kronenberger, T.; Müller, C. E.; Hanson, J. Structure-Activity Relationships of Agonists for the Orphan G Protein-Coupled Receptor GPR27. Eur. J. Med. Chem. 2021, 225, 113777, 10.1016/j.ejmech.2021.113777
Ge, S.; Zhong, H.; Ma, X.; Zheng, Y.; Zou, Y.; Wang, F.; Wang, Y.; Hu, Y.; Li, Y.; Liu, W.; Guo, W.; Xu, Q.; Lai, Y. Discovery of Secondary Sulphonamides as IDO1 Inhibitors with Potent Antitumour Effects in Vivo. J. Enzyme Inhib. Med. Chem. 2020, 35 ( 1), 1240- 1257, 10.1080/14756366.2020.1765165
Xu, F.; Zhao, Y.; Zhou, H.; Li, C.; Zhang, X.; Hou, T.; Qu, L.; Wei, L.; Wang, J.; Liu, Y.; Liang, X. Synthesis and Evaluation of 3-(4-(Phenoxymethyl)Phenyl)Propanoic Acid and N-Phenylbenzenesulfonamide Derivatives as FFA4 Agonists. Bioorg. Med. Chem. Lett. 2020, 30 ( 24), 127650, 10.1016/j.bmcl.2020.127650
Silveira, F. F.; de Souza, J. O.; Hoelz, L. V. B.; Campos, V. R.; Jabor, V. A. P.; Aguiar, A. C. C.; Nonato, M. C.; Albuquerque, M. G.; Guido, R. V. C.; Boechat, N.; Pinheiro, L. C. S. Comparative Study between the Anti-P. Falciparum Activity of Triazolopyrimidine, Pyrazolopyrimidine and Quinoline Derivatives and the Identification of New PfDHODH Inhibitors. Eur. J. Med. Chem. 2021, 209, 112941, 10.1016/j.ejmech.2020.112941
Batra, N.; Rajendran, V.; Agarwal, D.; Wadi, I.; Ghosh, P. C.; Gupta, R. D.; Nath, M. Synthesis and Antimalarial Evaluation of [1, 2,3]-Triazole-Tethered Sulfonamide-Berberine Hybrids. ChemistrySelect 2018, 3 ( 34), 9790- 9793, 10.1002/slct.201801905
Kroeze, W. K.; Sassano, M. F.; Huang, X.-P.; Lansu, K.; McCorvy, J. D.; Giguère, P. M.; Sciaky, N.; Roth, B. L. PRESTO-Tango as an Open-Source Resource for Interrogation of the Druggable Human GPCRome. Nat. Struct. Mol. Biol. 2015, 22 ( 5), 362- 369, 10.1038/nsmb.3014
Zhou, X. E.; He, Y.; de Waal, P. W.; Gao, X.; Kang, Y.; Van Eps, N.; Yin, Y.; Pal, K.; Goswami, D.; White, T. A.; Barty, A.; Latorraca, N. R.; Chapman, H. N.; Hubbell, W. L.; Dror, R. O.; Stevens, R. C.; Cherezov, V.; Gurevich, V. V.; Griffin, P. R.; Ernst, O. P.; Melcher, K.; Xu, H. E. Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors. Cell 2017, 170 ( 3), 457- 469.e13, 10.1016/j.cell.2017.07.002
Pandey, S.; Kumari, P.; Baidya, M.; Kise, R.; Cao, Y.; Dwivedi-Agnihotri, H.; Banerjee, R.; Li, X. X.; Cui, C. S.; Lee, J. D.; Kawakami, K.; Maharana, J.; Ranjan, A.; Chaturvedi, M.; Jhingan, G. D.; Laporte, S. A.; Woodruff, T. M.; Inoue, A.; Shukla, A. K. Intrinsic Bias at Non-Canonical, β-Arrestin-Coupled Seven Transmembrane Receptors. Mol. Cell 2021, 81 ( 22), 4605- 4621.e11, 10.1016/j.molcel.2021.09.007
Jang, W.; Lu, S.; Xu, X.; Wu, G.; Lambert, N. A. The Role of G Protein Conformation in Receptor-G Protein Selectivity. Nat. Chem. Biol. 2023, 19, 687- 694, 10.1038/s41589-022-01231-z
Liebing, A.-D.; Krumbholz, P.; Stäubert, C. Protocol to Characterize Gi/o and Gs Protein-Coupled Receptors in Transiently Transfected Cells Using ELISA and cAMP Measurements. STAR Protoc. 2023, 4 ( 1), 102120, 10.1016/j.xpro.2023.102120
Schihada, H.; Shekhani, R.; Schulte, G. Quantitative Assessment of Constitutive G Protein-Coupled Receptor Activity with BRET-Based G Protein Biosensors. Sci. Signal. 2021, 14 ( 699), eabf1653 10.1126/scisignal.abf1653
Ahad, A. Md.; Zuohe, S.; Du-Cuny, L.; Moses, S. A.; Zhou, L. L.; Zhang, S.; Powis, G.; Meuillet, E. J.; Mash, E. A. Development of Sulfonamide AKT PH Domain Inhibitors. Bioorg. Med. Chem. 2011, 19 ( 6), 2046- 2054, 10.1016/j.bmc.2011.01.049
Li, J.; Chen, J.; Gui, C.; Zhang, L.; Qin, Y.; Xu, Q.; Zhang, J.; Liu, H.; Shen, X.; Jiang, H. Discovering Novel Chemical Inhibitors of Human Cyclophilin A: Virtual Screening, Synthesis, and Bioassay. Bioorg. Med. Chem. 2006, 14 ( 7), 2209- 2224, 10.1016/j.bmc.2005.11.006
Roy, A.; Kucukural, A.; Zhang, Y. I-TASSER: A Unified Platform for Automated Protein Structure and Function Prediction. Nat. Protoc. 2010, 5 ( 4), 725- 738, 10.1038/nprot.2010.5
Chen, V. B.; Arendall, W. B.; Headd, J. J.; Keedy, D. A.; Immormino, R. M.; Kapral, G. J.; Murray, L. W.; Richardson, J. S.; Richardson, D. C. MolProbity: All-Atom Structure Validation for Macromolecular Crystallography. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66 ( 1), 12- 21, 10.1107/S0907444909042073
Sherman, W.; Beard, H. S.; Farid, R. Use of an Induced Fit Receptor Structure in Virtual Screening. Chem. Biol. Drug Des. 2006, 67 ( 1), 83- 84, 10.1111/j.1747-0285.2005.00327.x
Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004, 47 ( 7), 1739- 1749, 10.1021/jm0306430
Halgren, T. A. Identifying and Characterizing Binding Sites and Assessing Druggability. J. Chem. Inf. Model. 2009, 49 ( 2), 377- 389, 10.1021/ci800324m
Bowers, K. J.; Chow, E.; Xu, H.; Dror, R. O.; Eastwood, M. P.; Gregersen, B. A.; Klepeis, J. L.; Kolossvary, I.; Moraes, M. A.; Sacerdoti, F. D.; Salmon, J. K.; Shan, Y.; Shaw, D. E. Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters. SC ′06: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing; ACM: New York, NY, USA, 2006.
Lu, C.; Wu, C.; Ghoreishi, D.; Chen, W.; Wang, L.; Damm, W.; Ross, G. A.; Dahlgren, M. K.; Russell, E.; Von Bargen, C. D.; Abel, R.; Friesner, R. A.; Harder, E. D. OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space. J. Chem. Theory Comput. 2021, 17 ( 7), 4291- 4300, 10.1021/acs.jctc.1c00302
Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of Simple Potential Functions for Simulating Liquid Water. J. Chem. Phys. 1983, 79 ( 2), 926- 935, 10.1063/1.445869
Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: An N·log(N) method for Ewald sums in large systems. J. Chem. Phys. 1993, 98 ( 12), 10089- 10092, 10.1063/1.464397
Jacobson, M. P.; Pincus, D. L.; Rapp, C. S.; Day, T. J. F.; Honig, B.; Shaw, D. E.; Friesner, R. A. A Hierarchical Approach to All-Atom Protein Loop Prediction. Proteins 2004, 55 ( 2), 351- 367, 10.1002/prot.10613
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