Dual-targeting approach on histamine H3 and sigma-1 receptor ligands as promising pharmacological tools in the treatment of CNS-linked disorders.

Abstract:

: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.

journal_name

Curr Med Chem

authors

Szczepańska K,Kuder KJ,Kieć-Kononowicz K

doi

10.2174/0929867327666200806103144

subject

Has Abstract

pub_date

2020-08-05 00:00:00

eissn

0929-8673

issn

1875-533X

pii

CMC-EPUB-108881

pub_type

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