Discovery of GPR183 Agonists Based on an Antagonist Scaffold

Abstract

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca 2 + mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five inhouse compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.

Migration mediated by the oxysterol receptor GPR183 depends on arrestin coupling but not receptor internalization

“…The compounds TUG-2201 and TUG-2202 were synthesized in house as previously described ( 27 ), whereas compound TUG-2292 was synthesized as described in data file S1. 7α,25-OHC was purchased from Merck (catalog no.…”

“…Further evidence that G proteins were not required for GPR183 internalization was that three G protein-biased GPR183 agonists (fig. S5)-TUG-2201, TUG-2202 [known as 91 and 92, respectively, from the original study (27)], and TUG-2292 (a newly synthesized GPR183 agonist; data file S1)failed to induce GPR183 internalization (Fig. 3H), although they activated G protein signaling (fig.…”

“…The correlation between GPR183 activation or abundance and disease states, together with the fact that GPCRs represent the largest group of pharmaceutically targeted proteins (24,25), point toward exploring GPR183 as a therapeutic target. Several groups have published synthetic GPR183 ligands, including both agonists and antagonists (26)(27)(28)(29)(30).…”

Ligand entry pathways control the chemical space recognized by GPR183

“…In this study, we combine in silico and in vitro experiments to elucidate the entrance gates of different GPR183 agonists namely the endogenous oxysterol 7α,25-OHC and two synthetic agonists. 17 Our study reveals important insights into how a receptor uses promiscuous entrance gates to recognize chemically diverse ligands, which has important implications for drug development endeavors.…”

Discovery of a First-in-Class GPR183 Antagonist for the Potential Treatment of Rheumatoid Arthritis

“…To date, only a few small-molecule agonists, − inverse agonists, and antagonists have been reported. Compounds 1 ( NIBR51 ) and 2 are two representative examples of agonists (Figure ).…”