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 6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT 6 R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT 6 R affinity and selectivity over 5-HT 1A R ( 13 - 15 ), 5-HT 7 R ( 14 and 15 ), and 5-HT 2A R ( 13 ). Compound 15 displayed high selectivity for 5-HT 6 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 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.