The histamine H3 receptor: from gene cloning to H3 receptor drugs

The therapeutic modulation of several actions of the biogenic amine histamine has proved to be medically effective and also financially profitable. Antagonists that target the histamine H1 receptor (H1R) or the H2 receptor, which are used in the treatment of allergic conditions and gastric-acid-related disorders, respectively, have been 'blockbuster' drugs for many years.Following the Human Genome Project, the family of histamine receptors has been extended to include four different G-protein-coupled receptors (GPCRs): the H1, H2, H3 and H4 receptors, and current expectations for the therapeutic potential of drugs that target the H3 and/or H4 receptor are high.The identification of the H3 receptor at the molecular level in 1999 has greatly facilitated drug discovery efforts to target the H3 receptor, and currently many pharmaceutical companies are active in this field.As reviewed in this article, many potent and relatively selective H3 receptor agonists and inverse agonists have now been developed. For both H3 receptor agonists and H3 receptor inverse agonists/antagonists, interesting activities in several preclinical models of important human diseases, including obesity, migraine, attention-deficit hyperactivity disorder, and inflammatory diseases, have been reported.