Abstract

The human histamine H₄-receptor (hH₄R) possesses high constitutive activity and, like the human H₁-receptor (hH₁R), is involved in the pathogenesis of type-I allergic reactions. The study aims were to explore the value of dual H₁/H₄R antagonists as antiallergy drugs and to address the question of whether H₁R ligands bind to hH₄R. In an acute murine asthma model, the H₁R antagonist mepyramine and the H₄R antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine (JNJ 7777120) exhibited synergistic inhibitory effects on eosinophil accumulation in the bronchoalveolar lavage fluid. At the hH₄R expressed in Sf9 insect cells, 18 H₁R antagonists and 22 H₁R agonists showed lower affinity to hH₄R than to hH₁R as assessed in competition binding experiments. For a small number of H₁R antagonists, hH₄R partial agonism was observed in the steady-state GTPase assay. Most compounds were neutral antagonists or inverse agonists. Twelve phenylhistamine-type hH₁R partial agonists were also hH₄R partial agonists. Four histaprodifen-type hH₁R partial agonists were hH₄R inverse agonists. Dimeric histaprodifen was a more efficacious hH₄R inverse agonist than the reference compound thioperamide. Suprahistaprodifen was the only histaprodifen acting as hH₄R partial agonist. Suprahistaprodifen was docked into the binding pocket of inactive and active hH₄R models in two different orientations, predominantly stabilizing the active state of hH₄R. Collectively, the synergistic effects of H₁R 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 H₁R/H₄R antagonists is a worthwhile and technically feasible goal for the treatment of type-I allergic reactions.