2. Academic Validation
  3. Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27

Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27

  • Eur J Med Chem. 2021 Dec 5:225:113777. doi: 10.1016/j.ejmech.2021.113777.
Thanigaimalai Pillaiyar 1,  Francesca Rosato 2,  Monika Wozniak 3,  Jeremy Blavier 4,  Maëlle Charles 4,  Céline Laschet 4,  Thales Kronenberger 5,  Christa E Müller 2,  Julien Hanson 6
Affiliations

Affiliations

  • 1 Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany; Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany. Electronic address: thanigaimalai.pillaiyar@uni-tuebingen.de.
  • 2 Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
  • 3 Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium; Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland.
  • 4 Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.
  • 5 Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany; Department of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Str. 14, Tübingen, 72076, Germany.
  • 6 Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium; Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
PMID: 34454125 DOI: 10.1016/j.ejmech.2021.113777
Abstract

GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called "Super-Conserved Receptors Expressed in the Brain" (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic β-cell Insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC50 6.34, Emax 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an Arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC50 6.85, Emax 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC50 6.04, Emax 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC50 5.99, Emax 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.

Keywords

Agonist; Atypical GPCR; GPR173; GPR27; GPR85; Orphan GPCR; SREB; Sulfonamide; Super-conserved receptors expressed in the brain.

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