Dual-targeting Approach on Histamine H 3 and Sigma-1 Receptor Ligands as Promising Pharmacological Tools in the Treatment of CNS-linked Disorders

• Published in: Current medicinal chemistry Vol. 28; no. 15; p. 2974
• Main Authors: Szczepańska, Katarzyna, Kuder, Kamil J, Kieć-Kononowicz, Katarzyna
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 2021
• Subjects: Central Nervous System Diseases - drug therapy; Histamine; Humans; Ligands; Receptors, Histamine H3; Receptors, sigma; Sigma-1 Receptor; sigma-1 receptors; dual-targeting ligands; Pitolistant; H3R pharmacophores; CNS pathologies; Histamine H3 receptors
• ISSN: 1875-533X

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