Synthesis and evaluation of new potential anti-pseudo-allergic agents.

Abstract

Pseudo-allergic reactions frequently occur following clinical drug use and sometimes even cause mortal danger. Mas-related G-protein-coupled receptor member X2 (MRGPRX2) is a novel receptor that mediates pseudo-allergy and is an important target in the treatment of allergies. However, to date, there are no synthetic small-molecule inhibitors that prevent anaphylactoid reactions through this pathway. Our preliminary research suggested that B10-S and mubritinib effectively inhibited LAD2 cells. Therefore, two novel derivatives were synthesized by integrating the active substructures of B10-S and mubritinib, according to the molecular docking results. The antiallergic inhibitory effects of the two compounds were preliminarily evaluated in vitro using β-hexosaminidase release, histamine release, and intracellular Ca2+ mobilization assays, and their binding sites on MRGPRX2 were analyzed by molecular docking. Both substances inhibited β-hexosaminidase and histamine release in LAD2 cells and decreased intracellular Ca2+ by inhibiting MRGPRX2 in MRGPRX2-HEK293 cells treated with C48/80 in a dose-dependent manner. The docking results suggested that the molecules could competitively bind to the active site on MRGPRX2 and Glu141, which were combined by C48/80. Our study indicated that the two compounds have potential anti-allergic properties, which may provide evidence that will facilitate the development of synthetic molecules with anti-pseudo-allergic activity for clinical use in the future.

• Authors: Jiayu Lu, Xiangjun Wang, Shuai Ge, Yajing Hou, Yuexin Lv, Huaizhen He, Cheng Wang
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 59 Pg. 128575 (03 01 2022) ISSN: 1464-3405 [Electronic] England
• PMID: 35065236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Allergic Agents
• MRGPRX2 protein, human
• Nerve Tissue Proteins
• Oxazoles
• Receptors, G-Protein-Coupled
• Receptors, Neuropeptide
• TAK-165
• Triazoles

Topics

• Anaphylaxis (drug therapy, metabolism)
• Anti-Allergic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Dose-Response Relationship, Drug
• HEK293 Cells
• Humans
• Hypersensitivity (drug therapy, metabolism)
• Molecular Structure
• Nerve Tissue Proteins (metabolism)
• Oxazoles (chemical synthesis, chemistry, pharmacology)
• Receptors, G-Protein-Coupled (metabolism)
• Receptors, Neuropeptide (metabolism)
• Structure-Activity Relationship
• Triazoles (chemical synthesis, chemistry, pharmacology)