ReviewKeynoteMajor advances in the development of histamine H4 receptor ligands
Introduction
The histamine receptor (HR) research field has historically been fuelled by breakthrough discoveries at an interval of 17 years, that is, the discovery of two distinct HR subtypes (H1R and H2R) in 1966 [1], the discovery of the H3R in 1983 [2] and the identification of the sequence of H4R in genome databases in 2000 3, 4, 5, 6, 7, 8. This subfamily of G-protein-coupled receptors (GPCRs) has obtained a reputation of being very rewarding by the blockbuster status that was reached by H1R and H2R targeted drugs (for treating allergic conditions and gastric ulcers, respectively). Currently, the pharmaceutical industry is intensively exploring the clinical potential of H3R and H4R ligands 9, 10. Although the pharmacological effects of the H3R were already known soon after its discovery in 1983, this receptor subtype was only embraced by the industry after the cloning of the human H3R (hH3R) cDNA by Lovenberg et al. 11, 12. Following this discovery, several groups identified the H4R sequence in human genome databases on the basis of its homology with the H3R (31% at the protein level, 54% within the transmembrane domains). To date, two additional non-7-TM H4R splice variants have been identified [13]. Interestingly, these splice variants do not seem to bind histaminergic ligands, but affect the functionality of the full-length (functional) human H4R (hH4R) isoform, probably by GPCR hetero-dimerization [13]. Major species differences have been identified by the cloning of the genes for mouse, rat, guinea-pig, pig and, more recently, the dog and monkey H4R 14, 15.
The H4R receptor is mainly expressed in bone marrow and peripheral leukocytes, and mRNAs of the hH4 receptor are detected in for example, mast cells, dendritic cells, spleen and eosinophils 3, 4, 5, 6, 7. The H4 receptor has pronounced effects on the chemotaxis of several cell types that are associated with immune and inflammatory responses. Based on these early results from H4R characterization, both industry and academia initiated an effective search for potent and selective hH4R ligands and started to explore the therapeutic potential of such compounds. This has led to a steady output of both H4R-related patents and publications (Fig. 1).
Section snippets
H4R agonists
Most imidazole-containing H3R ligands that were developed in the 1980s and 1990s turned out to have significant affinity for the H4R as well [9]. For example, the H3R reference agonist, (R)-α-methylhistamine (2), was found to be only 40-fold selective for the H3R [9]. Another frequently used H3R agonist, immepip (3), shows only 40-fold selectivity for the H3R [16]. Structural modifications of immepip resulted in the potent and selective H3R compounds, immethridine [17] and methimepip (4) [16],
H4R antagonists
In the search for novel H4R antagonists or inverse agonists, a variety of ligand classes have been identified. An antagonist that was discovered shortly after cloning of the H4R gene in 2000 is the imidazole-containing ligand, thioperamide (13). Originally developed as an H3R antagonist, thioperamide (13) has an H4R affinity that is two to threefold lower than that for the H3R while acting as an H4R inverse agonist [20]. The early availability of recombinant systems to measure ligand affinity
Clinical applications for H4R antihistamines
H4R agonists and antagonists have an important role to play in the elucidation of the (patho)physiological role of the H4R and to explore the therapeutic potential of this receptor in human disease. The use of H4R ligands in animal models, so far mostly done with reference antagonist JNJ7777120 (14), has yielded a variety of interesting results.
Pruritis
Recently the role of the H1R and H4R in the attenuation of pruritis (itch) has been reported in several papers 60, 61, 62. In mice, the selective H4R agonist 4-MeHA (7) was shown to induce itch in a dose-dependent way and this effect could be blocked by the pretreatment with JNJ7777120 (14) [61]. The antipruritic effect of 14 was far superior to other antihistamines and only the centrally acting H1R antagonist diphenhydramine showed some antipruritic activity. This pruritic response could not
Asthma
A role for the H4R in a murine ovalbumin-induced inflammation model of asthma was recently found by Dunford et al. [63]. It was demonstrated that the H4R is involved in the activation of CD4+ cells by dendritic cells. The administration of JNJ7777120 (14) showed significant anti-inflammatory responses during both the sensitization and effector phases. This finding indicates that the H4R is involved in the initial priming of the immune system after allergen challenge. More importantly, the
Allergic rhinitis
The presence of the H4R in nasal tissue was first discovered by Nakaya et al. [64]. In addition, a more recent finding showed that there is a significant increase in the level of H4R in human nasal polyp tissue taken from patients with chronic rhinosinusitis (infection of the nose and nasal cavities) when compared to normal nasal mucosa [65]. Jókúti et al. suggest that the administration of H4R antagonists might be a new way to treat nasal polyps and chronic rhinosinusitis. The administration
Pain
In 2007 it was suggested that the H4R might play a role in nociception [68]. The H4R antagonist JNJ7777120 (14) and its benzimidazole analog, VUF6002 (15), were both able to increase paw withdrawal latency in carrageenan-induced thermal hyperalgesia in rats [68]. This effect on the modulation of pain was recently confirmed by work from Abbott Laboratories that describes in vivo anti-nociceptive effects of the H4R antagonist A-943931 (39) [55]. This compounds is active against
Cancer
Although histamine has been known to play a role in the development of cancer, a role for the H4R has only recently been suggested on the basis of in vitro studies with HT29 and Caco-2 cells [70]. Histidine decarboxylase is often overexpressed in human colorectal cancer cells, resulting in an increased local production of histamine from the amino acid histidine. The selective H4R antagonist JNJ7777120 (14) was able to inhibit histamine-induced overexpression of cyclooxygenase-2 and subsequent
Inflammatory bowel disease
In an experimental model of colitis in the rat, the oral administration of a high dose of the H4R antagonists JNJ7777120 (14) or VUF6002 (15) was able to reduce (TBNS)-induced colon damage, the influx of neutrophils and levels of myeloperoxidase in colonic tissue [72]. Although several of the underlying physiological mechanisms need to be fully explored, these preliminary findings suggest a potential role for H4R antagonists in inflammatory bowel disease.
Conclusions and outlook
Since the discovery of the H4R in 2000 the amount of publications and patent applications has shown a steady annual increase. Several useful selective H4R agonists and antagonists have been developed and now serve as important tools to delineate the role of the H4R in physiology and to establish its potential value as a drug target. The recent increase in patent applications from various players in the pharmaceutical industry clearly reflects the mounting interest in this new HR subtype as a
Dr Rogier Smits received his MSc in pharmacy and PharmD from the Rijksuniversiteit Groningen in the Netherlands. He then moved to Amsterdam to join the group of Rob Leurs, where he received a PhD in pharmacochemistry in 2009. He has recently cofounded an academic spin-out company called Griffin Discoveries that focuses on the development of small molecule drugs that target GPCRs.
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Dr Rogier Smits received his MSc in pharmacy and PharmD from the Rijksuniversiteit Groningen in the Netherlands. He then moved to Amsterdam to join the group of Rob Leurs, where he received a PhD in pharmacochemistry in 2009. He has recently cofounded an academic spin-out company called Griffin Discoveries that focuses on the development of small molecule drugs that target GPCRs.
Prof Dr Rob Leurs obtained his PhD in pharmacochemistry from the VU University Amsterdam in 1991. As a postdoctoral fellow (1992–1993) at INSERM (Unite de Neurobiologie and Pharmacologie, Paris), he was involved in the cloning of genes encoding histaminergic and serotonergic receptors. Thereafter, he was awarded with a five-year fellowship (1993–1998) of the Royal Netherlands Academy of Arts and Sciences. He was appointed as assistant and full professor in Medicinal Chemistry in 1998 and 2000.
Dr Iwan de Esch received an MSc in organic chemistry and holds a PhD in pharmacochemistry. In 1998, he joined the Drug Design Group of the University of Cambridge, UK. This group spun out of the university to form De Novo Pharmaceuticals. Iwan returned to academia in 2003 and is now an associate professor at the Medicinal Chemistry Department of the VU University Amsterdam.