Discovery of Tricyclic Xanthines as Agonists of the Cannabinoid-Activated Orphan G-Protein-Coupled Receptor GPR18

Clara T Schoeder; Andhika B Mahardhika; Anna Drabczyńska; Katarzyna Kieć-Kononowicz; Christa E Müller

doi:10.1021/acsmedchemlett.0c00208

Discovery of Tricyclic Xanthines as Agonists of the Cannabinoid-Activated Orphan G-Protein-Coupled Receptor GPR18

ACS Med Chem Lett. 2020 Jun 17;11(10):2024-2031. doi: 10.1021/acsmedchemlett.0c00208. eCollection 2020 Oct 8.

Authors

Clara T Schoeder^{1

2}, Andhika B Mahardhika^{1

2}, Anna Drabczyńska³, Katarzyna Kieć-Kononowicz³, Christa E Müller¹

Affiliations

¹ Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn 53121, Germany.
² Research Training Group 1873, University of Bonn, 53127 Bonn, Germany.
³ Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

Abstract

GPR18 is a rhodopsin-like orphan G-protein-coupled receptor (GPCR) that is activated by the natural cannabinoid (CB) Δ⁹-tetrahydrocannabinol (THC). It is highly expressed in immune cells and represents a promising new drug target. However, THC is much more potent in activating CB receptors than GPR18, and several other proposed lipidic agonists for GPR18 have not been independently confirmed. Herein we describe the first non-lipid-like agonists for GPR18 based on a tricyclic xanthine-derived scaffold, along with initial structure-activity relationships. PSB-KD107 (5) and PSB-KD477 (16) displayed significantly higher potency and efficacy than THC, determined in a GPR18-dependent β-arrestin recruitment assay, and were found to be selective versus the CB-sensitive receptors CB₁, CB₂, and GPR55. Structure-activity relationships were steep, and indole substitution was crucial for biological activity. These first selective agonists, which are structurally distinct from the lipidic agonist(s), will allow target validation studies and may eventually contribute to the deorphanization of GPR18.