Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency

  • J Med Chem. 2023 Dec 7. doi: 10.1021/acs.jmedchem.3c02030.
Thanigaimalai Pillaiyar  1 ,  Monika Wozniak  2 ,  Dayana Abboud  2 ,  Alexander Rasch  1 ,  Aenne-Dorothea Liebing  3 ,  Antti Poso  1  4  5 ,  Thales Kronenberger  1  4  5 ,  Claudia Stäubert  3 ,  Stefan A Laufer  1  4 ,  Julien Hanson  2  6
Affiliations
  • 1. Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 2. Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, B-4000 Liège, Belgium.
  • 3. Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany.
  • 4. Cluster of Excellence iFIT (EXC 2180) "Image-Guided & Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany.
  • 5. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • 6. Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, B-4000 Liège, Belgium.
PMID: 38060818 DOI: 10.1021/acs.jmedchem.3c02030
Abstract

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.

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