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

Thanigaimalai Pillaiyar; Francesca Rosato; Monika Wozniak; Jeremy Blavier; Maëlle Charles; Céline Laschet; Thales Kronenberger; Christa E Müller; Julien Hanson

doi:10.1016/j.ejmech.2021.113777

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. Epub 2021 Aug 14.

Authors

Thanigaimalai Pillaiyar¹, Francesca Rosato², Monika Wozniak³, Jeremy Blavier⁴, Maëlle Charles⁴, Céline Laschet⁴, Thales Kronenberger⁵, Christa E Müller², Julien Hanson⁶

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, E_max 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, E_max 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC₅₀ 6.04, E_max 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC₅₀ 5.99, E_max 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.

MeSH terms

Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology*
Cell Survival / drug effects
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Models, Molecular
Molecular Structure
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Benzamides
Receptors, G-Protein-Coupled