First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT 6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT emerged as a promising target for AD treatment; thus, here a new series of 5-HT R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl d...

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Published in:Journal of medicinal chemistry 2024-01, Vol.67 (2), p.1580-1610
Main Authors: Pyka, Patryk, Haberek, Wawrzyniec, Więcek, Małgorzata, Szymanska, Ewa, Ali, Wesam, Cios, Agnieszka, Jastrzębska-Więsek, Magdalena, Satała, Grzegorz, Podlewska, Sabina, Di Giacomo, Silvia, Di Sotto, Antonella, Garbo, Sabrina, Karcz, Tadeusz, Lambona, Chiara, Marocco, Francesco, Latacz, Gniewomir, Sudoł-Tałaj, Sylwia, Mordyl, Barbara, Głuch-Lutwin, Monika, Siwek, Agata, Czarnota-Łydka, Kinga, Gogola, Dawid, Olejarz-Maciej, Agnieszka, Wilczyńska-Zawal, Natalia, Honkisz-Orzechowska, Ewelina, Starek, Małgorzata, Dąbrowska, Monika, Kucwaj-Brysz, Katarzyna, Fioravanti, Rossella, Nasim, Muhammad Jawad, Hittinger, Marius, Partyka, Anna, Wesołowska, Anna, Battistelli, Cecilia, Zwergel, Clemens, Handzlik, Jadwiga
Format: Article
Language:English
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Summary:Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT emerged as a promising target for AD treatment; thus, here a new series of 5-HT R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT R affinity and selectivity over 5-HT R ( - ), 5-HT R ( and ), and 5-HT R ( ). Compound displayed high selectivity for 5-HT R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c02148