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

Abstract

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 /H 4 R antagonists as antiallergy drugs and to address the question of whether H 1 R ligands bind to hH 4 R. In an acute murine asthma model, the H 1 R antagonist mepyramine and the H 4 R 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 H 1 R antagonists and 22 H 1 R agonists showed lower affinity to hH 4 R than to hH 1 R as assessed in competition binding experiments. For a small number of H 1 R 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 H 1 R and H 4 R antagonists in an acute asthma model and the overlapping interaction of structurally diverse H 1 R ligands with hH 1 R and hH 4 R indicate that the development of dual H 1 R/H 4 R antagonists is a worthwhile and technically feasible goal for the treatment of type-I allergic reactions.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…In mouse models of asthma, H 4 receptor antagonists reduced eosinophilia and Th2 responses (Dunford et al, 2006;Deml et al, 2009;Cowden et al, 2010a;Somma et al, 2013). However, the story may not be as straightforward as it first appeared, because a locally administered H 4 R/H 2 receptor agonist was protective in another mouse asthma study and these effects may have been mediated via enhanced recruitment of regulatory T cells via the H 4 receptor (Morgan et al, 2007).…”

“…The number of H 3 receptor isoforms possible Vollinga et al (1994). Sharif et al (1996) Data from Harada et al (1983); Gantz et al (1991b); Leurs et al (1994aLeurs et al ( , 1995b; Sharif et al (1996) d Data from Ligneau et al, 2000;Liu et al, 2001b;Morse et al, 2001;Zhu et al, 2001;O'Reilly et al, 2002;Esbenshade et al, 2003;Thurmond et al, 2004Thurmond et al, , 2014aLim et al, 2005;Gbahou et al, 2006;Ligneau et al, 2007;Nagase et al, 2008;Zhao et al, 2008;Deml et al, 2009;Sander et al, 2009;Mowbray et al, 2011;Rossbach et al, 2011;Appl et al, 2012;Shin et al, 2012;Andaloussi et al, 2013;Savall et al, 2014 Fig. 10).…”

Analysis of Histamine Receptor Knockout Mice in Models of Inflammation

“…Finally, agonists and antagonists for all histamine receptor subtypes are used experimentally in basic and preclinical research . Nevertheless, the use of histamine receptor subtype-selective ligands has to be interpreted with caution because the specificity, efficacy, and potency are not always as unproblematic as originally assumed (Deml et al, 2009;Neumann et al, 2010;Reher et al, 2012a;Seifert et al, 2013). Therefore, to unambiguously investigate the role of a specific histamine receptor subtype, the use of genetic knockout models is important.…”

Structure-based discovery and binding site analysis of histamine receptor ligands

“…More recently the binding mode of H1 agonists and antagonists at the H4R binding site were analyzed to identify dual H1/H4 acting ligands [49]. Eighteen H1 antagonists and 22 H1 agonists showed lower affinity to hH4R than to hH1R.…”