gpr18/gpr55

Anandamide ((5Z,8Z,11Z,14Z)-N-(2-Hydroxyethyl)icosa-5,8,11,14-tetraenamide), an immune modulator, acts via not only cannabinoid receptors (CB1 and CB2) but also other targets (e.g., GPR18 GPR55) in the central nervous system.

PSB-KD477 is an Agonist of the Cannabinoid-Activated Orphan G-Protein-Coupled Receptor GPR18. PSB-KD477 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.

PSB-KK1445 is a potent and selective agonist of GPR18, exhibiting EC50 values of 45.4 nM for humans and 124 nM for mice. The selectivity of PSB-KK1445 for GPR18 over the CB receptor subtypes GPR55 and GPR183 exceeds 200-fold.