RT Journal Article
SR Electronic
T1 Interactions of Histamine H<sub>1</sub>-Receptor Agonists and Antagonists with the Human Histamine H<sub>4</sub>-Receptor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1019
OP 1030
DO 10.1124/mol.109.058651
VO 76
IS 5
A1 Deml, Karl-Friedrich
A1 Beermann, Silke
A1 Neumann, Detlef
A1 Strasser, Andrea
A1 Seifert, Roland
YR 2009
UL http://molpharm.aspetjournals.org/content/76/5/1019.abstract
AB 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. © 2009 The American Society for Pharmacology and Experimental Therapeutics