With the recent market approval of Pitolisant (Wakix®), the interest in clinical application
for novel multifunctional histamine H3 receptor antagonists has clearly increased.
Several combinations of different H3R pharmacophores with pharmacophoric elements of
other G-protein coupled receptors, transporters, or enzymes have been synthesized by numerous
pharmaceutical companies and academic institutions. Since central nervous system disorders
are characterized by diverse physiological dysfunctions and deregulations of a complex
network of signaling pathways, optimal multipotent drugs should simultaneously and peculiarly
modulate selected groups of biological targets. Interestingly, very recent studies have
shown that some clinically evaluated histamine H3 receptor antagonists possess a nanomolar
affinity for sigma-1 receptor binding sites, suggesting that this property might play a role in
their overall efficacy. The sigma-1 receptor, unusual and yet obscure protein, is supposed to
be involved in numerous CNS pathologies through neuroprotection and neuroplasticity. These
two different biological structures, histamine H3 and sigma-1 receptors, combined, can represent
a potential fruitful target for therapeutic developments in tackling numerous human diseases.