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. (2009) 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 H 1 (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 -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 British Journal of Pharmacology

Functional pharmacology of H1 histamine receptors expressed in mouse preoptic/anterior hypothalamic neurons

“…Histamine modulates a variety of centrally controlled physiological functions, such as arousal, attention, sleep, feeding and thermoregulation (Haas and Panula, ). Recent advances in histamine receptor research have provided new drug targets in the CNS (Chazot, ). Thus, histamine H 3 receptor antagonists have been proposed as candidates for the treatment of cognitive (Jin et al ., ; Chazot, ) and sleep disorders (Guo et al ., ).…”

Phthalazin-1(2H)-one as a remarkable scaffold in drug discovery

“…It is noteworthy that antagonists for H 1 R and H 2 R subtype have been for many years blockbusters in therapy of allergic conditions and gastric ulcer, respectively, and that several H 3 R and H 4 R antagonists are currently in different stages of preclinical or clinical development [93].…”

“…Allergic rhinitis and allergic processes in general are mediated by histamine, an intracellular chemical messenger which is released from several cells and specifically by mast cells [93]. [96].…”

Histamine: an undercover agent in multiple rare diseases?

“…These observed phenomena occur because the antihistamines that are currently used in the clinic have little, if any, affinity for H 4 R. Thurmond et al [9] suggest that there is a need to develop better H 4 R modulators to revisit the potential of antihistamines against inflammatory diseases, including the newly identified ones. Lots of different research groups are working towards achieving a complete biochemical and pharmacological characterization of this novel Hia receptor [10,37,38].…”