Contributors: 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, Mariu; Partyka, Anna; Wesołowska, Anna; Battistelli, Cecilia; Zwergel, Clemen; Handzlik, Jadwiga
نبذة مختصرة : Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT6R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT6R affinity and selectivity over 5-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (13). Compound 15 displayed high selectivity for 5-HT6R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 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, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15'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.
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