[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 [DE] DFG - Deutsche Forschungsgemeinschaft [DE] MWK - Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg [DE] F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Universität Leipzig [DE]
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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