作者
Patryk Pyka,Wawrzyniec Haberek,Małgorzata Więcek,Ewa Szymańska,Wesam Ali,Agnieszka Cios,Magdalena Jastrzębska-Więsek,Grzegorz Satała,Sabina Podlewska,Silvia Di Giacomo,Antonella Di Sotto,Sabrina Garbo,Tadeusz Karcz,Chiara Lambona,Francesco Marocco,Gniewomir Latacz,Sylwia Sudoł-Tałaj,Barbara Mordyl,Monika Głuch‐Lutwin,Agata Siwek,Kinga Czarnota-Łydka,Dawid Gogola,Agnieszka Olejarz-Maciej,Natalia Wilczyńska-Zawal,Ewelina Honkisz-Orzechowska,Małgorzata Starek,Monika Dąbrowska,Katarzyna Kucwaj-Brysz,Rossella Fioravanti,Muhammad Jawad Nasim,Marius Hittinger,Anna Partyka,Anna Wesołowska,Cecilia Battistelli,Clemens Zwergel,Jadwiga Handzlik
摘要
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.