Histamine H₃ receptor ligands break ground in a remarkable plethora of therapeutic areas

The neurotransmitter histamine exerts its action through four distinct histamine receptors. The histamine H₁ and H₂ receptor are well established drug targets, whereas the histamine H₄ receptor is undergoing rigorous characterisation at present. The histamine H₃ receptor (H₃R) is a G_i/o-protein coupled receptor and is mostly expressed in the CNS. A remarkably large and different array of therapeutic areas, in which ligands for the H₃R may prove useful, has been identified and a massive research undertaking is underway to substantiate the high expectations for H₃R ligands. At present, several ligands for the H₃R are being evaluated in clinical studies. In this review, the many potential therapeutic areas for H₃R antagonists, inverse agonists and agonists is discussed. Promising medicinal chemistry and toxicological developments, as well as the advancement of several H₃R ligands into the clinic, will be highlighted. This review also describes the problems that have been overcome and the questions that remain in developing H₃R-related drugs. Considering the tremendous efforts by industry, it can be expected that the first H₃R drugs will reach the market soon.