jnj-7777120 and Hypersensitivity

Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.

Topics: Aminopyridines; Animals; Arthritis, Rheumatoid; Asthma; Dermatitis, Atopic; Drug Partial Agonism; Histamine Agonists; Histamine Antagonists; Humans; Hypersensitivity; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Structure-Activity Relationship

Substantial evidence implicates mast cells and their main constituent histamine in the pathogenesis of visceral hypersensitivity. We explored the specific contribution of histamine H4 (H4R) and H1 (H1R) receptors to visceral hypersensitivity in a postinflammatory rat model.. Trinitrobenzenesulfonic acid (TNBS)-colitis was monitored individually by colonoscopy: first on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Experiments were performed 3 days after endoscopic resolution of colitis. Visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. Colonic mast cell numbers, histamine release and H4R and H1R mRNA expression were quantified. JNJ7777120 (H4R antagonist) and/or levocetirizine (H1R antagonist) were administered 30 min prior to VMR assessment or histamine release assay.. Postcolitis rats displayed a higher number of colonic mast cells, excessive histamine release and significantly enhanced VMRs. Heightened VMRs were dose-dependently reduced by JNJ7777120 and levocetirizine; combined administration of JNJ7777120 and levocetirizine potentiated the antinociceptive effect. In the colon, both H4R and H1R mRNA were present; in the dorsal root ganglia, only H1R mRNA was found. Only colonic H4R mRNA expression was increased in postcolitis rats. Excessive histamine release in postcolitis rats was attenuated by the highest dose of JNJ7777120.. H4R and H1R antagonists dose-dependently reduce and even normalise postinflammatory visceral hypersensitivity via different underlying mechanisms but with a synergistic effect. Both receptor subtypes represent promising targets for the treatment of postinflammatory visceral hypersensitivity.

Topics: Animals; Cetirizine; Colitis; Colonoscopy; Convalescence; Disease Models, Animal; Histamine; Histamine H1 Antagonists, Non-Sedating; Histamine Release; Hypersensitivity; Indoles; Intestinal Mucosa; Male; Mast Cells; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H4; Regeneration; Trinitrobenzenesulfonic Acid

The histamine H(4) receptor is a G protein-coupled receptor that has attracted much interest for its role in inflammatory and immunomodulatory functions. In our search for new H(4)R ligands, a low affinity isoquinoline fragment was optimized to 7-(furan-2-yl)-4-(piperazin-1-yl)quinazolin-2-amine (VUF11489), as a new H(4)R antagonist. Analysis of its binding kinetics at the human H(4)R showed this compound to have a very different dissociative half-life in comparison with reference antagonist JNJ7777120.

Topics: Animals; Biological Availability; Chemistry, Pharmaceutical; Drug Design; Histamine Antagonists; Humans; Hypersensitivity; Inhibitory Concentration 50; Kinetics; Ligands; Mice; Models, Chemical; Models, Molecular; Molecular Conformation; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Structure-Activity Relationship; Time Factors

Dendritic cells are potential targets in allergy therapy as they, under the influence of their microenvironment, regulate T-cell responses. Histamine has been shown to promote Th2 polarization by dendritic cells. However, neither the mechanism nor the functionality of the different histamine receptors in this process has been fully elucidated. The aim of the present study was to identify factors involved in histamine-mediated dendritic cell activation as well as to study dendritic cell expression of histamine H(1) and H(4) receptors and their influence on allergen-specific T-cell responses in grass pollen allergy. Assessment of dendritic cell gene regulation by histamine using mRNA microarrays demonstrated that histamine alters many immunoregulatory genes of which the majority are novel in this context. Additionally, immunocytochemical stainings showed protein expression of histamine H(1) and H(4) receptors on dendritic cells from healthy and allergic donors. Furthermore, histamine H(1) and H(4) receptor antagonists (pyrilamine/N-(4-methoxybenzyl)-N',N'-dimethyl-N-pyridin-2-ylethane-1,2-diamine and JNJ7777120/1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine, respectively) were shown to influence histamine-induced dendritic cell maturation. Interestingly, JNJ7777120 inhibited dendritic cells' capacity to induce allergen-specific T-cell proliferation. In conclusion, H(4) receptor antagonism suppressed DC-induced, allergen-specific T-cell responses in humans and might thus inhibit allergic responses. This finding indicates that the H(4) receptor is a potential treatment target in human allergic conditions.

Topics: Adult; Allergens; Case-Control Studies; Dendritic Cells; Female; Gene Expression Regulation; Histamine; Humans; Hypersensitivity; Indoles; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Piperazines; Pyrilamine; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H4; T-Lymphocytes; Transcription, Genetic; Young Adult