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

Abstract

The histamine H 4 receptor (H 4 R) 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 H 4 R agonists have not been identified. In the present study, we therefore evaluated the human H 4 R (hH 4 R) for its interaction with various known histaminergic ligands. Almost all of the tested H 1 R and H 2 R antagonists, including several important therapeutics, displaced less than 30% of specific [3 H]histamine binding to the hH 4 R at concentrations up to 10 M. Most of the tested H 2 R agonists and imidazolebased H 3 R ligands show micromolar-to-nanomolar range hH 4 R affinity, and these ligands exert different intrinsic hH 4 R activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity H 4 R ligand (K i ϭ 50 nM) that has a Ͼ100-fold selectivity for the hH 4 R over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the hH 4 R (pEC 50 ϭ 7.4 Ϯ 0

Histamine reverses IL-5-afforded human eosinophil survival by inducing apoptosis: Pharmacological evidence for a novel mechanism of action of histamine

“…Moreover, during receptor. [19,37] Moreover, at least some antagonism by thioperamide, JNJ7777120 and MMPCI would have been expected at the H 4 receptor [19,35] even though histamine was used with a much higher concentration than its affinity for the H 4 receptor subtype [19]. In previous studies evaluating the H 4 receptor-mediated effects of histamine on eosinophils, the A c c e p t e d m a n u s c r i p t effects of similar histamine concentrations were antagonized with similar thioperamide and JNJ7777120 concentrations and agonized with similar clobenpropit concentrations as used in the present study.…”

“…[19] However, evidence suggesting the existence of the histamine H 3 receptors on human eosinophils is now known to be incorrect. [1,45,46] Indeed, the novel histamine receptor discovered in eosinophils by Raible and co-workers in the 1990s [45,46] has now been identified as the H 4…”

“…Thioperamide is also an antagonist of the histamine H 4 receptor at concentrations in the low micromolar range (K i ~ 0.13 µM) [13,16,17,19] and was examined on eosinophil apoptosis in the absence and presence of histamine (100 µM) and IL-5 (1 pM). As shown in figure 5A, thioperamide did not reverse the effect of histamine but slightly attenuated the rate of apoptosis in general at the highest concentration (10 µM) studied (Fig.…”

“…5B). To exclude the possibility that the high concentration of histamine (100 µM) used in these experiments would, by competition, limit the degree of antagonism produced by JNJ7777120, we also tested the effect of 10 µM JNJ7777120 on eosinophil apoptosis induced by 10 µM nM [37]; clobenpropit = 8 nM [19]). …”

“…A fifth histamine receptor, located intracellularly and denoted histamine H IC , has also been described in haematopoietic cells. [18] Histamine binds to the different receptor subtypes with markedly different affinity: the K i -values range from 5-15 nM for the histamine H 3 and H 4 receptor subtypes [10,11,19] to approximately 10-100 µM for histamine H 1 , H 2 and H IC [10,11,18,19]. The four cell surface histamine receptor subtypes transduce extracellular signals by using a variety of G-proteins and intracellular second-messenger systems.…”