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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 peculiary modulate selected groups of biological targets. Interestingly, very recent studies have shown
that some of clinically evaluated histamine H3 receptor antagonists possess 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 potential fruitful target for therapeutic developments in tackling numerous human diseases.