PSB-22034

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 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 Bu 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-Me derivative 31d (PSB-22040, EC50, 19.2/30.0 nM) showing high selectivity vs. all other MRGPRX subtypes.They present promising tool compounds for exploring the potential of MRGPRX4 as a future drug target.Synthesis of phosphoric acid derivatives 17d, 19d, and 21b-dReagents and conditions: (a) 3-iodopropyl acetate, K2CO3, DMF, rt, 24 h; (b) P2O5, DMF, 100°C, 10-30 min; (c) CH3I, K2CO3, DMF, rt, 6 h; (d) KOH/methanol/H2O; (e) PO(OMe)3/POCl3, rt, 30 min, H2O.Chem. structures and potencies of xanthine derivatives as MRGPRX4 agonistsEC50 values are shown in bold.Data are means of at least three independent experiments performed in duplicates.LN229 glioblastoma cells naturally expressing MRGPRX4-83S were used.CHO-β-arrestin-MRGPRX4-83S cells were used. 1321N1 astrocytoma recombinantly expressing the MRGGPRX4-83L were employed.Determined in CHO-β-arrestin-MRGPRX4-83L cells.