Discovery of Potent Agonists for the Predominant Variant of the Orphan MAS-Related G Protein-Coupled Receptor X4 (MRGPRX4)

The
MAS-related Gq 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-(m-methoxyphenethyl)-1-propargylxanthine substituted with a butyl linker
in the 3-position containing a terminal phosphonate (30d, PSB-22034, EC50 Ca2+ assay/β-arrestin
assay, 11.2 nM/32.0 nM) and its N7-methyl derivative 31d (PSB-22040, EC50, 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.