Molecular determinants of selective agonist and antagonist binding to the histamine H₄ receptor

Enade P Istyastono, Chris de Graaf, Iwan J P de Esch, Rob Leurs

Research output: Contribution to JournalReview articleAcademicpeer-review


The deorphanization of the histamine H₄ receptor (H₄R) has led to a significant number of scientific publications and patent applications. Whereas some histamine H₁, H₂ and H₃ receptor ligands were found to have significant affinity for H₄R, several agonists and antagonists with high affinity for H₄R and selectivity over the other histamine receptors were successfully designed and synthesized. Moreover, site-directed mutation studies on H₄R have been performed and reveal detailed information on receptor-ligand interactions. This review will focus on the most important H₄R ligand scaffolds and their structure-activity relationships and selectivity over other histamine receptors and specific H₄R functional activity. Experimental data are used to construct and validate high resolution three-dimensional receptor-ligand models and, vice versa, in silico models are used to design and rationalize experimental studies to probe receptor-ligand interactions.

Original languageEnglish
Pages (from-to)661-79
Number of pages19
JournalCurrent Topics in Medicinal Chemistry
Issue number6
Publication statusPublished - 2011


  • Binding Sites
  • Histamine Agonists
  • Histamine Antagonists
  • Humans
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Structure-Activity Relationship
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Review


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