Perspective The histamine H 4 receptor: Targeting inflammatory disorders Miriam Walter, Tim Kottke, Holger Stark ⁎ Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biocenter, ZAFES/LiFF/CMP/ICNF, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany abstract article info Article history: Received 7 April 2011 Received in revised form 7 June 2011 Accepted 15 June 2011 Available online 3 July 2011 Keywords: Histamine H 4 receptor Antagonist Allergy Autoimmune disease Inflammation Immunology The discovery of the histamine H 4 receptor has added a new chapter to the century of extensive biogenic amine research. The human histamine H 4 receptor is mainly expressed in cells of the human immune system (e.g. mast cells, eosinophils, monocytes, dendritic cells, T cells) and mediates several effects on chemotaxis with numerous cell types. The distinct expression pattern and the immunomodulatory role highlight its physiological relevance in inflammatory and immunological processes. Inflammatory conditions, e.g. allergy, asthma and autoimmune diseases, were for a long time thought to be mainly mediated by activation of the histamine H 1 receptor subtype. However, in the treatment of diseases as chronic pruritus, asthma and allergic rhinitis the use of histamine H 1 receptor antagonists is unsatisfying. Selective H 4 receptor ligands and/or synergism of histamine H 1 and H 4 receptor modulation may be more effective in such pathophysiological conditions. Promising preclinical studies underline its role as an attractive target in the treatment of inflammatory and autoimmune disorders. Meanwhile, first histamine H 4 receptor antagonist has reached clinical phases for the treatment of respiratory diseases. © 2011 Elsevier B.V. All rights reserved. 1. History Histamine plays an important role as neurotransmitter and chemical mediator in a multitude of central and peripheral (patho) physiological processes. In the last century extensive study of its actions in the human body, resulted in detection of four G protein- coupled receptor subtypes (histamine H 1 –H 4 receptors) (Parsons and Ganellin, 2006). In 1994, Raible and co-workers identified histamine induced pertussis toxin-sensitive cytosolic calcium 2+ increase in eosinophils, which could be inhibited by histamine H 3 receptor inverse agonist thioperamide and induced by (R)-α-methylhistamine (agonist) in lower potency (Raible et al., 1994). Histamine H 3 receptor independent uptake and release of histamine by hematopoietic progenitor cells was unaffected by histamine H 3 receptor agonists, indicating a further histamine receptor subtype (Corbel et al., 1997). First, the long-awaited cloning of the histamine H 3 receptor gene in 1999 enabled detection and proof of a fourth histamine receptor responsible for the observed effects. In 2000–2001 several research groups independently identified an unexplored sequence in the human genome as new histamine H 4 receptor (cf. Zampeli and Tiligada, 2009). The subsequent discovery of the selective acting inverse agonist/antagonist JNJ7777120 (Jablonowski et al., 2003) give an important pharmacological tool for the characterization of the receptor and enabled the investigation of its pathophysiological role in the development of various diseases. Lately, findings concerning partial agonism of JNJ7777120 (Rosethorne and Charlton, 2010) and functional selectivity of the receptor have challenged its use as “standard” histamine H 4 receptor antagonist (Seifert et al., 2011). Since the cloning and pharmacological characterization of the histamine H 4 receptor, preclinical and clinical studies underlined its role as an attractive target in the treatment of inflammatory and autoimmune diseases (Tiligada et al., 2009; Vives et al., 2010). 2. Molecular structure The human histamine H 4 receptor gene, encoding for a 390 amino acid protein, is localized on chromosome 18 and contains three exons, interrupted by two introns. Whereas such intron–exon distribution resulted in a multitude of histamine H 3 receptor isoforms, so far only three non-signaling H 4 receptor isoforms have been reported, possibly acting as negative regulatory element on full-length receptor function (van Rijn et al., 2008). The histamine H 4 receptor protein possesses all consensus motifs identified for class A rhodopsin-like G protein- coupled receptors similar to the other histamine receptor subtypes. So far, structure-based as well as computer-aided investigations revealed some similarities in ligand-receptor interactions of histamine H 3 and H 4 receptor, leading to dual acting imidazole-containing histamine H 3 /H 4 receptor ligands (Kottke et al., 2011). Due to structural relatedness imidazole-containing compounds and the endogenous ligand histamine bind in a comparable manner to both targets (Jongejan et al., 2008; Schlegel et al., 2007). Scaffold optimization of diaminopyrimidines led to functional-varying histamine H 4 receptor ligands (Sander et al., 2009) based on their receptor binding mode (Werner et al., 2010). Depending on the identification of the human European Journal of Pharmacology 668 (2011) 1–5 ⁎ Corresponding author. Fax: + 49 69 79829258. E-mail address: h.stark@pharmchem.uni-frankfurt.de (H. Stark). 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.06.029 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar