Development of Potent G Protein Pathway-Biased GPR183 Agonists

Abstract GPR183 is an oxysterol-sensing GPCR predominantly expressed in lymphoid organs and tissues. Activation of the receptor by oxysterol 7α,25-OHC leads to Gα i protein-mediated signaling as well as β-arrestin2 recruitment. GPR183/oxysterol signaling modulates localization of lymphoid cells, consequently the receptor is associated with several inflammation-associated diseases and is an interesting potential drug target. Previously, we reported the discovery of moderately potent G protein-biased partial agonists for GPR183 from a virtual screening based on the scaffold of the antagonist NIBR189. Herein, we present the detailed structure-activity investigations and optimizations, which led to the identification of full agonists for GPR183 with complete bias for Gα i protein signaling and low nanomolar potency, including 63 (TUG-2604) with potency and efficacy similar to 7α,25-OHC. Notably, 63 was unable to induce migration of human dendritic cells but inhibited migration induced by 7α,25-OHC. This compound will be valuable for further explorations of the signaling-specific function and drug target potential of GPR183.