Se-containing 5-HT₆R ligands in search for efficient therapy of Alzheimer's disease

Serotonin 5-HT₆ receptor has been an attractive protein target for over 20 years in the search for new therapeutic agents for the treatment of the central nervous system disorders, including depression and Alzheimer's disease (AD). Nonetheless, none from already designed 5-HT₆R agents have reached pharmaceutical market yet. This is enhanced by deficiency of effective treatment for AD, and therefore new drugs development becomes an urgent need. Searching for highly active 5-HT­₆R ligands with desired pharmacokinetic profile is demanding in this field. Additionally, very recent studies have emphasized the neuroprotective properties of selenium-containing derivatives, which may turn out to be very useful for treatment of neurodegenerative disorders such as AD.

Previously we obtained the group of highly active 5-HT₆R ligands among triazine derivatives with a procognitive effect in vivo, which contained oxygen or sulphur as heteroatom in linker. The aim of this study was to investigate how the presence of selenium will affect the in vitro activity. Hence, the subject of the presented research is a series of novel triazine-based selenium-containing derivatives varying in different length and branching of the linker.

Structure-activity relationship analysis, performed within this study, led to the highlighting the differences of presented derivatives from already synthesized O- and S- containing 5-HT₆R ligands and to determine structural factors which provide such activity among this original chemical class of compounds. Finally, the novel Se-containing derivatives with the most promising activity will be selected for further in silico and in vitro evaluation of ADMET and neuroprotective properties.