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

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.