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

The human histamine H-4-receptor (hH(4)R) possesses high constitutive activity and, like the human H-1-receptor (hH(1)R), is involved in the pathogenesis of type-I allergic reactions. The study aims were to explore the value of dual H-1/H4R antagonists as antiallergy drugs and to address the question of whether H1R ligands bind to hH(4)R. 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 hH(4)R expressed in Sf9 insect cells, 18 H1R antagonists and 22 H1R agonists showed lower affinity to hH(4)R than to hH(1)R as assessed in competition binding experiments. For a small number of H1R antagonists, hH(4)R partial agonism was observed in the steady-state GTPase assay. Most compounds were neutral antagonists or inverse agonists. Twelve phenylhistamine-type hH(1)R partial agonists were also hH(4)R partial agonists. Four histaprodifen-type hH(1)R partial agonists were hH(4)R inverse agonists. Dimeric histaprodifen was a more efficacious hH(4)R inverse agonist than the reference compound thioperamide. Suprahistaprodifen was the only histaprodifen acting as hH(4)R partial agonist. Suprahistaprodifen was docked into the binding pocket of inactive and active hH(4)R models in two different orientations, predominantly stabilizing the active state of hH(4)R. Collectively, the synergistic effects of H1R and H4R antagonists in an acute asthma model and the overlapping interaction of structurally diverse H1R ligands with hH(1)R and hH(4)R indicate that the development of dual H1R/H4R antagonists is a worthwhile and technically feasible goal for the treatment of type-I allergic reactions.