Furanocoumarin derivatives inhibit MRGPRX2-mediated pseudo-allergy

Mas-related G protein-coupled receptor X2 (MRGPRX2) is a novel G protein-coupled receptor (GPCR) that has been identified as a potential therapeutic target for pseudo allergic diseases. The development of novel MRGPRX2 antagonists possesses tremendous therapeutic and social implications. Recent efforts have been invested in finding specific MRGPRX2 inhibitors for potential therapeutic approaches, although none has been approved for clinical use to date. We previously identified Imperatorin (the furanocoumarin compound) as a lead molecule for MRGPRX2 antagonist. In this study, we investigated the anti-pseudo-allergic effect of the fourteen synthesized furanocoumarin derivatives, as well as the relationship between their activity and MRGPRX2 receptor. In vitro and in vivo experimental results showed that compounds XAT-13 and XAT-14 can suppress compound 48/80-induced Mast cells degranulation in a good dose-dependent manner. Molecular docking implied that XAT-13 and XAT 14 may shared the same binding sites with C48/80. Our study revealed that the novel small molecules (XAT-13 and XAT-14) as early-stage lead compounds, which can be further optimized to obtain therapeutic drug candidates to address MRGPRX2 mediated allergic reactions and other inflammatory diseases.