In vitro and in vivo characterization of A‐940894: a potent histamine H₄ receptor antagonist with anti‐inflammatory properties

Abstract

Background and purpose:The histamine H4 receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti-inflammatory properties of a potent histamine H4 receptor antagonist, A-940894 (4-piperazin-1-yl-6,7-dihydro-5H-benzo [6,7]Experimental approach: We have analysed the pharmacological profile of A-940894 at mouse native, rat recombinant and human recombinant and native, histamine H4 receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan-induced peritonitis. Key results: A-940894 potently binds to both human and rat histamine H4 receptors and exhibits considerably lower affinity for the human histamine H1, H2 or H3 receptors. It potently blocked histamine-evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine-induced shape change of mouse bone marrow-derived mast cells and chemotaxis of human eosinophils in vitro. In a mouse mast cell-dependent model of zymosan-induced peritonitis, A-940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D2 levels. Finally, A-940894 has good pharmacokinetic properties, including half-life and oral bioavailability in rats and mice. Conclusions and Implications: These data suggest that A-940894 is a potent and selective histamine H4 receptor antagonist with pharmacokinetic properties suitable for long-term in vivo testing and could serve as a useful tool for the further characterization of histamine H4 receptor pharmacology.

The Histamine H4 Receptor: A Novel Target for Safe Anti-inflammatory Drugs?

“…70 In line with this, in several experimental models of intestinal damage, H 4 R antagonists were able to reduce neutrophil infiltration in intestinal mucosa. 19,21,24,[62][63][64] The gastric safety of H 4 R antagonists could be of major interest, when considering that the available anti-inflammatory drugs are still endowed with gastric toxicity; 14 nevertheless, the precise role of H 4 R in the gastric mucosa remains to be proven, since data with selective ligands are intriguing: the H 4 R agonist VUF8430…”

“…[18][19][20][21][22][23][24] histAMinE h 4 R liGAnDs Since H 3 R and H 4 R are closely related, the early physiopharmacological characterization of the H 4 R was based on compounds retaining the ability to bind the H 3 R subtype. 25 The first selective H 4 R antagonist was the indolylpiperazine compound, JNJ7777120, which displayed high affinity (K i = 4 nM) for the human H 4 R with and a >1000-fold selectivity over the other histamine receptors, 26 thus becoming the "reference" H 4 R ligand in most experimental assays, also due to the lack of highly selective H 4 R agonists.…”

Development of a Profiling Strategy for Metabolic Mixtures by Combining Chromatography and Mass Spectrometry with Cell-Based GPCR Signaling

“…25,26 Compounds with no supplier reference were synthesized in-house at the VU University Medicinal Chemistry department.…”

Advances in histamine pharmacology reveal new drug targets

“…In an original publication from Lim et al (2009), a new improved selective H4 receptor agonist is reported, which will prove invaluable in the pharmacological dissection of this highly topical new drug target. A second original article from Strakhova et al (2009) reports the detailed pharmacological properties of a new potent highly selective H4 receptor antagonist, which adds to the range of pharmacophores available to study this histamine receptor. Improved pharmacokinetic properties displayed by this ligand should aid in its potential clinical use for chronic inflammatory disorders.…”

“…In an original publication from Lim et al (2009), a new improved selective H4 receptor agonist is reported, which will prove invaluable in the pharmacological dissection of this highly topical new drug target. A second original article from Strakhova et al (2009) reports the detailed pharmacological properties of a new potent highly …”