2. Academic Validation
  3. Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency

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

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.

Figures
Products