Development and Chemistry of Histamine H4 Receptor Ligands as Potential Modulators of Inflammatory and Allergic Responses

J.   D.   Venable; R.   L.   Thurmond

Abstract

Histamine, which is known to play a role in most inflammatory conditions including allergy, asthma and autoimmune diseases, is a ubiquitous chemical messenger that has numerous functions. The inflammatory responses of histamine have long been believed to be mainly mediated by the histamine H1 receptor. Indeed the importance of histamine in the pathology of many diseases, like asthma, has been defined by whether traditional antihistamines, which are H1 receptor antagonists, are efficacious. The discovery of a fourth histamine receptor (H4) has prompted the questioning of these assumptions. The H4 receptor is expressed on mast cells, eosinophils, basophils, dendritic cells and T cells suggesting that it may play an important role in inflammatory responses. The discovery of selective ligands for this receptor has been crucial in uncovering its function. These tools have been used to show that the receptor plays a role in mast cell and eosinophil chemotaxis, as well as cytokine production in dendritic cells and T cells. In addition H4 receptor antagonists have efficacy in a variety of inflammatory animal models including peritonitis, colitis and airway inflammation models. These data suggest that the H4 receptor is an attractive medicinal chemistry target for possible treatment of inflammation, allergy and asthma. Herein we describe the recent advances regarding the biology of the histamine H4 receptor, as well as detail the progress in developing imidazole and non-imidazole based modulators of this receptor as anti-inflammatory therapies.

Keywords: Asthma, pruritus, colitis, G-protein coupled receptor, antihistamine, mast cells, dendritic cells, eosinophils