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Objective <p>The histamine H1 receptor (H1R) plays a central role in mediating allergic responses, making it a critical target for therapeutic intervention. However, the molecular mechanisms underlying drug binding to H1R remain incompletely elucidated.</p> Methods <p>We employed an integrated approach combining site-directed mutagenesis, cell membrane chromatography (CMC) and pharmacological activity assays to systematically characterize the binding mechanisms of H1R agonists and antagonists. We constructed various H1R/CMC systems using high-expression H1R cells (wild type, TM3, TM5, TM6, and ECL2 mutants) and evaluated the binding affinities of three agonists (histamine, HTMT, betahistine) and three classes of antagonists (ethylenediamine/propanamine, tricyclic, piperidine derivatives).</p> Results <p>Our findings reveal distinct agonist binding preferences: histamine primarily targets TM3, HTMT interacts with TM5, and betahistine shows a strong preference for TM6. Among antagonists, ethylenediamine/propanamine and piperidine classes predominantly block TM3 and TM6 regions, while tricyclic antagonists additionally depend on TM5 region for their inhibitory effects. Pharmacological validation through phospholipase C (PLC) activity assays corroborated these results, demonstrating that mutations in specific transmembrane domains significantly alter agonist-induced signaling and antagonist-mediated efficacy.</p> Conclusion <p>These mechanistic insights into H1R ligand binding provide a structural foundation for the rational design of targeted therapies with improved selectivity and efficacy against allergic disorders.</p>

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Investigation of the Binding Characteristics of Agonists and Various Antagonists Targeting Histamine 1 Receptor

  • 期刊论文

  • 发表日期：

    2025年8月4日

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  • Panpan Lei,
  • Yuxiu Zhang,
  • Xiaoyu Ma,
  • Sifan Xie,
  • Jiapan Gao,
  • Bingxi Ren,
  • Yuanji Wang,
  • Weina Ma

摘要

Objective

The histamine H1 receptor (H1R) plays a central role in mediating allergic responses, making it a critical target for therapeutic intervention. However, the molecular mechanisms underlying drug binding to H1R remain incompletely elucidated.

Methods

We employed an integrated approach combining site-directed mutagenesis, cell membrane chromatography (CMC) and pharmacological activity assays to systematically characterize the binding mechanisms of H1R agonists and antagonists. We constructed various H1R/CMC systems using high-expression H1R cells (wild type, TM3, TM5, TM6, and ECL2 mutants) and evaluated the binding affinities of three agonists (histamine, HTMT, betahistine) and three classes of antagonists (ethylenediamine/propanamine, tricyclic, piperidine derivatives).

Results

Our findings reveal distinct agonist binding preferences: histamine primarily targets TM3, HTMT interacts with TM5, and betahistine shows a strong preference for TM6. Among antagonists, ethylenediamine/propanamine and piperidine classes predominantly block TM3 and TM6 regions, while tricyclic antagonists additionally depend on TM5 region for their inhibitory effects. Pharmacological validation through phospholipase C (PLC) activity assays corroborated these results, demonstrating that mutations in specific transmembrane domains significantly alter agonist-induced signaling and antagonist-mediated efficacy.

Conclusion

These mechanistic insights into H1R ligand binding provide a structural foundation for the rational design of targeted therapies with improved selectivity and efficacy against allergic disorders.