1. Academic Validation
  2. Potent, Selective Agonists for the Cannabinoid-like Orphan G Protein-Coupled Receptor GPR18: A Promising Drug Target for Cancer and Immunity

Potent, Selective Agonists for the Cannabinoid-like Orphan G Protein-Coupled Receptor GPR18: A Promising Drug Target for Cancer and Immunity

  • J Med Chem. 2024 Jun 27;67(12):9896-9926. doi: 10.1021/acs.jmedchem.3c02423.
Andhika B Mahardhika 1 2 3 Michal Załuski 4 Clara T Schoeder 1 2 Nader M Boshta 1 Jakub Schabikowski 4 Filomena Perri 1 2 Dorota Łażewska 4 Alexander Neumann 1 2 Sarah Kremers 1 Angelo Oneto 1 Anastasiia Ressemann 1 Gniewomir Latacz 4 Vigneshwaran Namasivayam 1 Katarzyna Kieć-Kononowicz 4 Christa E Müller 1 2 3
Affiliations

Affiliations

  • 1 Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
  • 2 Research Training Group 1873, University of Bonn, 53127 Bonn, Germany.
  • 3 Research Training Group 2873, University of Bonn, 53121 Bonn, Germany.
  • 4 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Pl 30-688 Kraków, Poland.
Abstract

The human orphan G protein-coupled receptor GPR18, activated by Δ9-tetrahydrocannabinol (THC), constitutes a promising drug target in immunology and Cancer. However, studies on GPR18 are hampered by the lack of suitable tool compounds. In the present study, potent and selective GPR18 agonists were developed showing low nanomolar potency at human and mouse GPR18, determined in β-arrestin recruitment assays. Structure-activity relationships were analyzed, and selectivity versus cannabinoid (CB) and CB-like receptors was assessed. Compound 51 (PSB-KK1415, EC50 19.1 nM) was the most potent GPR18 agonist showing at least 25-fold selectivity versus CB receptors. The most selective GPR18 agonist 50 (PSB-KK1445, EC50 45.4 nM) displayed >200-fold selectivity versus both CB receptor subtypes, GPR55, and GPR183. The new GPR18 agonists showed minimal species differences, while THC acted as a weak partial agonist at the mouse receptor. The newly discovered compounds represent the most potent and selective GPR18 agonists reported to date.

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