Evaluation of Histamine H1-, H2-, and H3-Receptor Ligands at the Human Histamine H4 Receptor: Identification of 4-Methylhistamine as the First Potent and Selective H4 Receptor Agonist

  title={Evaluation of Histamine H1-, H2-, and H3-Receptor Ligands at the Human Histamine H4 Receptor: Identification of 4-Methylhistamine as the First Potent and Selective H4 Receptor Agonist},
  author={Herman D. Lim and Richard M. van Rijn and Ping Ling and Remko A. Bakker and Robin L. Thurmond and Rob Leurs},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  pages={1310 - 1321}
  • H. LimR. V. van Rijn R. Leurs
  • Published 1 September 2005
  • Biology, Chemistry
  • Journal of Pharmacology and Experimental Therapeutics
The histamine H4 receptor (H4R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H4R agonists have not been identified. In the present study, we therefore evaluated the human H4R (hH4R) for its interaction with various known histaminergic ligands. Almost all of the tested H1R and H2R antagonists, including several important therapeutics, displaced less than 30% of specific… 

Tables from this paper

Interactions of Histamine H1-Receptor Agonists and Antagonists with the Human Histamine H4-Receptor

The synergistic effects of H 1R and H4R antagonists in an acute asthma model and the overlapping interaction of structurally diverse H1R ligands with hH1R and hH4R indicate that the development of dual H1/H4r antagonists is a worthwhile and technically feasible goal for the treatment of type-I allergic reactions.

Agonist-Biased Signaling at the Histamine H4 Receptor: JNJ7777120 Recruits β-Arrestin without Activating G Proteins

It is demonstrated that JNJ7777120 recruits β-arrestin to the H4 receptor, independent of G protein activation, suggesting little difference in the levels of receptor reserve between the two assays.

Compared pharmacology of human histamine H3 and H4 receptors: structure–activity relationships of histamine derivatives

Although the pharmacological profiles of the human H3R and H4R overlap, the structure–activity relationships of histamine derivatives at both receptors strongly differ and lead to the identification of selective compounds.

Histamine H4 receptor ligands

The objective of this review is to compile currently available H4R ligands and to present noticeable structure-activity and structure-selectivity relationships as well as some selected functional and (pre)clinical data.

Molecular Determinants of Ligand Binding to H4R Species Variants

The H4R orthologs expressed in human embryonic kidney 293T cells are a useful reference for ligand selection for studies in animal models of diseases and offer new insights in the understanding of H 4R-ligand receptor interactions.

Role of the second and third extracellular loops of the histamine H4 receptor in receptor activation

Molecular dynamic simulations suggest that the E2- and E3-loops are independently of each other involved in the partial/inverse agonism of JNJ7777120 and that E 2- as well as E 3-loop do not directly interact with JNJ 7777120 in the binding pocket.

Paradoxical Stimulatory Effects of the “Standard” Histamine H4-Receptor Antagonist JNJ7777120: the H4 Receptor Joins the Club of 7 Transmembrane Domain Receptors Exhibiting Functional Selectivity

Novel findings can be explained within the concept of functional selectivity or biased signaling, assuming unique ligand-specific receptor conformations with distinct signal transduction capabilities, and great caution must be exerted when interpreting in vivo effects of JNJ7777120 as H4R antagonism.

Docking and MD study of histamine H4R based on the crystal structure of H1R.

Clobenpropit analogs as dual activity ligands for the histamine H 3 and H 4 receptors : Synthesis , pharmacological evaluation , and cross-target QSAR studies Adapted from :

The synthesis and pharmacological characterization of a series of clobenpropit analogs, which vary in the functional group adjacent to the isothiourea moiety in order to study structural requirements for H3R and H4R ligands are described.

Histamine H4 receptor agonists.




A Potent and Selective Histamine H4 Receptor Antagonist with Anti-Inflammatory Properties

The results indicate that the histamine H4 receptor plays a role in the inflammatory process and may have the potential to be useful in treating inflammation in humans.

Chemical differentiation of histamine H1- and H2-receptor agonists.

2-(2-aminoethyl)thiazole and 2-aminosine are nontautomeric and are highly selective agonists for histamine H1 receptors (H1:H2 ca. 90:1 and 30:1, respectively).

Histamine H4 and H2 Receptors Control Histamine-Induced Interleukin-16 Release from Human CD8+ T Cells

Agonists selective for H2 (dimaprit), H3/4 (R-(−)-α-methylhistamine), and H4 (clobenpropit) were capable of inducing the release of bioactive IL-16 because CD8+ cell supernatants induced CD4+ cell migration, which was abrogated by an anti-IL-16 antibody.

Synthesis and pharmacological identification of neutral histamine H1-receptor antagonists.

Several compounds with partial inverse agonistic properties and two neutral H(1)-receptor antagonists are identified by screening newly synthesized ligands that are structurally related to H( 1)R agonists for their affinity using radioligand displacement studies and by assessing their functional activity via performing a NF-kappaB driven reporter-gene assay.

Histamine h(4) and h(2) receptors control histamine-induced interleukin-16 release from human CD8(+) T cells.

Histamine stimulation of human CD8(+) T lymphocytes purified from peripheral blood led to a 5- to 8-fold increase in the basal release of IL-16 within 24 h, and this increase was significantly blocked by the H(2)-selective antagonist, cimetidine, or by thioperamide, an antagonist of H(3) and H(4) receptors, respectively.

8R-lisuride is a potent stereospecific histamine H1-receptor partial agonist.

8R-lisuride is the most potent stereospecific partial agonist for the human H1R yet reported, and provides a valuable tool to further characterize this important therapeutic target in vitro.


A novel G protein-coupled receptor, termed Pfi-013, is identified and cloned from an IL-5 stimulated eosinophil cDNA library which is homologous to the human histamine H3 receptor, both at the sequence and gene structure level.

Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in BalbC mice

Results indicate that activation of histamine H4 receptors causes itch in mice, in addition to the previously recognised role for H1 receptors in evoking itch, and Histamines H4 receptor antagonists merit investigation as antipruritic agents.

Constitutive activity of histamine h(3) receptors stably expressed in SK-N-MC cells: display of agonism and inverse agonism by H(3) antagonists.

Receptor affinity was reduced slightly for most impentamine analogs, but the functional activity of the ligands varied from agonist to neutral antagonist and inverse agonist, indicating that subtle changes in the chemical structures of impentamines analogs have major impact on the (de)activation steps of the H(3) receptor.