Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics

Naunyn Schmiedebergs Arch Pharmacol. 2012 Feb;385(2):145-70. doi: 10.1007/s00210-011-0704-0. Epub 2011 Oct 28.


Antidepressants and antipsychotics affect multiple molecular targets. Consequently, these drugs exhibit not only unique profiles of therapeutic effects but also several undesired effects. Histamine receptors (H₁R, H₂R, H₃R, and H₄R) belong to the large family of G protein-coupled receptors and are very important drug targets. All four H(x)R subtypes are expressed in the CNS. Interactions of lipophilic, blood-brain barrier-penetrating drugs with H(x)Rs could contribute to therapeutic and unwanted effects. Therefore, we investigated potencies H(x)R as well as potencies and (inverse) agonistic efficacies of 34 antidepressants and antipsychotics at HxRs in functional assays. We expressed human H(x)Rs in Sf9 insect cells and conducted radioligand competition binding experiments and functional steady-state GTPase assays. Ligand affinities and potencies were compared with literature data and related to therapeutic reference ranges. Almost all antidepressants and antipsychotics displayed high binding affinities to H₁R and behaved as antagonists. The atypical antidepressant trimipramine behaved as a high-affinity/high-potency H₂R antagonist (pK(i), 7.39; pK(B), 7.36; pA₂, 7.55). Docking to an H₂R model suggested a probable binding mode. The affinity of antidepressants and antipsychotics for H₃R was low. The atypical antipsychotic clozapine, known to induce agranulocytosis, exhibited partial H₄R agonism for which docking experiments provided a molecular basis. Clozapine also exhibited H₂R antagonism. We observed dissociations between pK(i) and pK (B) values as well as between pK(i) and pIC₅₀ values for H(x)Rs. Antidepressants and antipsychotics interact differentially with H(x)Rs. The concept of functional selectivity (also referred to as ligand-specific receptor conformations or biased signaling) explains dissociations between pK(i) and pK(B) values as well as differences between pK(i) and pIC₅₀ values. The H₁R antagonism of numerous antidepressants and antipsychotics is very pronounced. The H₂R antagonism of trimipramine and partial H₄R agonism of clozapine may be clinically relevant. We also discuss the possible role of the H₂R antagonism of clozapine for neutropenia/agranulocytosis induced by this compound. Finally, we discuss the methodological, conceptual, and clinical limitations of our study.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents / metabolism*
  • Antipsychotic Agents / metabolism*
  • Binding, Competitive
  • Histamine Agonists / metabolism
  • Histamine Antagonists / metabolism
  • Humans
  • Models, Molecular
  • Protein Binding
  • Radioligand Assay
  • Receptors, Histamine / metabolism*
  • Recombinant Proteins / metabolism


  • Antidepressive Agents
  • Antipsychotic Agents
  • Histamine Agonists
  • Histamine Antagonists
  • Receptors, Histamine
  • Recombinant Proteins