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 H(1) and H(2) receptor are well established drug targets, whereas the histamine H(4) receptor is undergoing rigorous characterisation at present. The histamine H(3) receptor (H(3)R) 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 H(3)R may prove useful, has been identified and a massive research undertaking is underway to substantiate the high expectations for H(3)R ligands. At present, several ligands for the H(3)R are being evaluated in clinical studies. In this review, the many potential therapeutic areas for H(3)R antagonists, inverse agonists and agonists is discussed. Promising medicinal chemistry and toxicological developments, as well as the advancement of several H(3)R ligands into the clinic, will be highlighted. This review also describes the problems that have been overcome and the questions that remain in developing H(3)R-related drugs. Considering the tremendous efforts by industry, it can be expected that the first H(3)R drugs will reach the market soon.