Advances in histamine pharmacology reveal new drug targets

Abstract

This Themed Issue consists of three reviews and 11 original articles authored by internationally respected industrial and academic pharmacologists from across three continents. It derives from the highly successful symposium on ‘The H₃ and H₄ histamine receptors: the antihistamines for the 21^st century’, which took place at EPHAR 2008 in Manchester University, and encompasses new roles, new compounds and exciting new therapeutic areas for histamine.

Histamine (2-(imidazol-4-yl) ethylamine) is found in most tissues of the body but is present in high concentrations in the lungs and the skin and in particularly high concentrations in the gastrointestinal tract. It is found mainly in mast cells and basophils, associated with heparin, but non-mast-cell histamine is also present in ‘histaminocytes’ in the stomach and in histaminergic neurons in the brain. Ever since the seminal studies using histamine by the father of modern-day pharmacology, Sir Henry Dale, in the early 1930s, the histaminergic system has proved to be one of the most productive areas for successful clinical pharmacology, proving a rich source of useful drugs, particularly over the last three decades. Antagonists for the histamine H₁ (fexofenadine in Allegra® or l-cetirizine in Xyzal®) or H₂ receptors (cimetidine in Tagamet® or ranitidine in Zantac®) have both reached blockbuster status and been successfully used for many years in the treatment of allergic conditions and gastric ulcers respectively. Currently, attention in the pharmaceutical industry is directed towards the therapeutic use of the newest members of the histamine receptor family, namely the H₃ and H₄ receptors. Histamine H₃ and H₄ receptor antagonists are currently in preclinical development and in early stages of clinical trials for a range of cognitive, psychotic, sleep and inflammatory disorders, obesity and cancers. A number of internationally renowned industrial and academic pharmacologists from Europe, the US and New Zealand appear in this Themed Issue that arose from the successful symposium ‘The H₃ and H₄ histamine receptors: the antihistamines for the 21^st century’ organized by myself and Dr Katherine Tiligada (University of Athens, Greece) at EPHAR 2008 in Manchester University. It brings together a rich array of review and original articles spanning medicinal chemistry and the molecular, behavioural and clinical pharmacology of histamine. A number of the leading pharmaceutical companies, including GSK, Abbott and Johnson and Johnson, together with academic drug developers from the Netherlands and Spain report in a series of original articles new pharmacological data for novel chemical structural leads for the H₃ and H₄ receptors, together with a review discussing a novel modelling strategy for developing histidine decarboxylase inhibitors as a proof of concept (Moya-García et al., 2009).

The two main reviews within this volume focus on the newest member of the histamine receptor family, namely the H₄ receptor, covering the latest findings relating to its molecular and biochemical pharmacology, from Leurs et al. (2009), and exciting roles in the immune system and in inflammation from Zampeli and Tiligada (2009). The histamine H₄ receptor is a highly topical drug target for a growing spectrum of therapeutic areas as evidenced by the recently successful funding of the European ESF COST Action BM0806 entitled ‘Histamine H₄ receptor research’ (HARR4-EU COST); many of the present authors being Management Committee members of this new action. In an original publication from Lim et al. (2009), a new improved selective H₄ receptor agonist is reported, which will prove invaluable in the pharmacological dissection of this highly topical new drug target. A second original article from Strakhova et al. (2009) reports the detailed pharmacological properties of a new potent highly selective H₄ receptor antagonist, which adds to the range of pharmacophores available to study this histamine receptor. Improved pharmacokinetic properties displayed by this ligand should aid in its potential clinical use for chronic inflammatory disorders. Connelly et al. (2009) have provided important new evidence that the H₄ receptor is not exclusively expressed on haematopoietic cells. Here, they report the first pharmacological evidence, using a selective H₄ receptor antagonist, for functional histamine H₄ receptors on cortical neurons. This adds to the growing evidence for the H₄ receptor subtype subserving distinct roles on multiple cell types in the body, which is further elaborated in the review by Leurs et al. (2009).

Oligomerization of G protein-coupled receptors (GPCRs) is a mature theme in pharmacology and the GPCRs of the histamine receptor family provide many examples of this phenomenon. As well as previously reported homo-oligomerization, hetero-oligomerization appears to be possible even with different GPCR families. In this volume, Ferrada et al. (2009) report evidence for the presence in vivo of the heteromeric partners, histamine H₃ and dopamine D₁ receptors, focusing on the issue of signal transactivation, a growing concept in GPCR pharmacology. The clinical relevance of such functional interactions is clear as both receptor families are implicated in a wide spectrum of clinical CNS disorders and diseases.

Manipulating the histaminergic system in the CNS is clearly a validated approach for many clinical indications, but the consequences for cognitive function require continuing attention. Blockade of histamine H₁ receptors has been previously implicated in learning deficits with the first generation anti-histamines. Here, van Ruitenbeek et al. (2009a) provide new evidence that hypofunction of the human central histaminergic system (through blockade of the H₁ receptor) reduced sensory, rather than motor information processing, and Zlomuzica et al. (2009) report that genetic inactivation of the H₁ receptor in the mouse leads to spatial working and reference memory impairments, while having no significant effect on emotional behaviour in the light–dark test. For the first time, van Ruitenbeek et al. (2009b) report the results of a study that decreased histamine levels, by depleting its precursor L-histidine, in human volunteers. This method was then used to study the role of histamine in cognitive performance. Although modest effects upon histamine levels and behavioural outcomes were observed, this clearly forms the basis for an interesting new protocol to study the effects of the depletion of histamine (and other monoamines) in the clinic.

The histamine H₃ receptor is highly expressed in a number of key structures in the mammalian and human CNS, and clearly subserves key modulatory roles, particularly those relating to sleep and feeding behaviours, attention and cognitive processing, as well as specific types of nociception and movement co-ordination (see Vohora, 2008). The growing physiological and pharmacological information has laid the foundation for the recent therapeutic advancement of compounds acting on central H₃ receptors. Narcolepsy is the first indication being assessed for H₃ receptor antagonists in the clinic, with a number of phase I and II trials ongoing. Acute dosing with such compounds has shown beneficial effects (increased wakefulness) in animal models of narcolepsy. In this Issue, Guo et al. (2009) provide important new evidence that selective H₃ receptor antagonists (in this case GSK189254) are still effective, even after repeated dosing, using the orexin-knock out mouse model of narcolepsy.

Another important clinical area in which targeting of the histamine H₃ receptor has been pursued is psychotic disorders, particularly related to the cognitive deficits seen in schizophrenia. Jin et al. (2009) report new findings that show an elevated level of H₃ receptors in the prefrontal cortex and reduced levels in the hippocampus, which project to many cortical and subcortical regions, which may explain the cognitive deficits seen within this patient group. Medhurst et al. (2009) reported the preservation of H₃ receptors in many key brain structures in cases of advanced Alzheimer's disease, but an elevated receptor level again in the prefrontal cortex, which correlated with increased severity of cognitive impairment. These two studies provide further new evidence to validate the use of histamine H₃ receptor antagonists for cognitive dysfunctions in a range of neurological and psychological disorders.

In order to maximize translation from preclinical optimism to clinical success, predictive assessments are vital. Miller et al. (2009) reported a useful alternative to current ex vivo approaches to measure receptor occupancy, which are fraught with problems, including dissociation of radiotracer during processing and the assay protocol, which reduces their utility. The in vivo method to assess receptor occupation described here relies on reduction of radiotracer levels in specific brain regions in comparison with vehicle-treated controls, based on scintillation counting, and is analogous to a PET/SPECT imaging system. Lack of suitable radiotracers to assess H₃ receptor occupancy, because of poor brain penetration and high non-specific binding, has negated the use of this methodology with the older H₃ receptor ligands; interestingly, these older ligands subsequently failed in the clinic. Using a newer, highly selective H₃ receptor radiotracer, the relationship between receptor occupancy and drug doses, blood exposure level and efficacy in behavioural tests could be established, demonstrating general utility of this methodology in preclinical assessment.

Overall, this topical Themed Issue highlights the rapid emergence of the targets for the next generation of anti-histamine drugs, namely the histamine H₃ and H₄ receptors, which hold significant promise in a wide range of clinical areas. The in vitro and in vivo pharmacological studies, together with new strategies for drug discovery, reported here confirm that there are exciting times ahead for histamine pharmacology.

Glossary

Abbreviations:

EPHAR

European Pharmacological Societies

ESF COST

European Science Foundation Cooperation in Science and Technology

PET

Positron emission tomography

SPECT

Single photon emission computed tomography