Abstract
With the very recent market approval of pitolisant (Wakix (R)), the interest in clinical applications of novel multifunctional histamine H-3 receptor antagonists has clearly increased. Since histamine H-3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H-3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.