Dual-targeting Approach on Histamine H3 and Sigma-1 Receptor Ligands as Promising Pharmacological Tools in the Treatment of CNS-linked Disorders

With the recent market approval of Pitolisant (Wakix®), the interest in clinical application for novel multifunctional histamine H 3 receptor antagonists has clearly increased. Several combinations of different H 3 R 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 H 3 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 H 3 and sigma-1 receptors, combined, can represent a potential fruitful target for therapeutic developments in tackling numerous human diseases.