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.
Processing Request
No Comments.