Papers of the Week

The MAS-related G protein-coupled receptor X4 (MRGPRX4) is poorly investigated. MRGPRX4 has been proposed to be involved in pain transmission, itch, inflammation, wound healing, and cancer. However, so far only a few moderately potent, nonselective MRGPRX4 agonists have been described, most of which appear to preferably activate the minor receptor variant MRGPRX4-83L but not the main variant 83S. In the present study, we discovered a xanthine derivative bearing a phosphate substituent that activates the main variant of MRGPRX4. Optimization resulted in analogs with high potency and metabolic stability. The best compounds of the present series include 8-(-methoxyphenethyl)-1-propargylxanthine substituted with a butyl linker in the 3-position containing a terminal phosphonate (, PSB-22034, EC Ca assay/β-arrestin assay, 11.2 nM/32.0 nM) and its N7-methyl derivative (PSB-22040, EC, 19.2/30.0 nM) showing high selectivity versus all other MRGPRX subtypes. They present promising tool compounds for exploring the potential of MRGPRX4 as a future drug target.