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

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.

The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects

“…GPR18 is clearly activated by the natural cannabinoid Δ 9 -tetrahydrocannabinol (THC). Endogenous agonists have been postulated, including AEA, its metabolite N-arachidonylglycine (NAGly), and resolvin D2, but these results are controversially discussed in the literature [ 10 , 11 ]. THC is a non-selective ligand for GPR18, it is much more potent as a partial CB 1 and CB 2 receptor agonist, and it additionally blocks GPR55, an orphan receptor that is activated by lysophosphatidylinositol.…”

“…Our latest studies have allowed us to identify new tool compounds for GPR18, which are selective, versus other cannabinoid receptors, including agonists [ 11 ] and antagonists [ 12 ]. Schoeder et al (2020) discovered the tricyclic xanthines PSB-KD-107 and PSB-KD477 as the first non-lipid-like agonists for GPR18.…”

“…Schoeder et al (2020) discovered the tricyclic xanthines PSB-KD-107 and PSB-KD477 as the first non-lipid-like agonists for GPR18. Moreover, these compounds displayed higher potency and efficacy than THC [ 11 ]. In addition, PSB-KK-1415 has recently been developed as a novel potent and selective cannabinoid receptors with increased potency agonist [ 4 , 14 ].…”

Effects of GPR18 Ligands on Body Weight and Metabolic Parameters in a Female Rat Model of Excessive Eating

“…GPR18, identified in 1997, has been reported to be activated by Δ 9 -tetrahydrocannabinol (THC), AEA [ 9 ], and N -arachidonylglycine—the endogenous metabolite of AEA [ 10 ] and resolvin D2 [ 11 ]. However, there are contradicting reports on several proposed putative GPR18 agonists [ 12 , 13 , 14 , 15 ], and the only one which is generally confirmed is THC; therefore, GPR18 has been considered as a third cannabinoid receptor [ 9 ]. GPR55 is proposed to be activated endogenously by lysophosphatidylinositol [ 16 ].…”

“…Since some researchers suggest the possible role of GPR18 in the progression of metabolic disease and obesity, this receptor and its ligands became a new potential therapeutic target [ 10 ]. So far, only few (mostly nonselective) GPR18 agonists [ 15 ] or antagonists have been described [ 21 , 22 , 23 ]. Our groups have recently developed potent and selective GPR18 agonists, e.g., compound PSB-KK1415.…”