First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT₆ Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) has a complex and notfully-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.

5-Ht6 Receptor Neutral Antagonists Protect Astrocytes a Lesson from 2-Phenylpyrrole Derivatives

“…The UPLC/MS purity of all the final compounds and key intermediates was confirmed to be 95 % or higher. 1 H NMR, 13 C NMR, 19 FNMR spectra were recorded with Varian BB 200 (300 and 75 MHz), Bruker Avance III (400 MHz and 101 MHz) or JEOL JNMECZR 500 RS1 (500, 471, and 126 MHz) and are reported in ppm using deuterated solvent for calibration (CDCl 3 , CD 3 OD or DMSO-d 6 ). The J values are reported in hertz (Hz), and the splitting patterns are designated as follows: br s (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), ddd (doublet of doublets of doublets), m (multiplet).…”

“…Recently developed 1,3, 5-triazine-based 5-HT 6 R antagonists have shown protective effects against rotenone-induced neurotoxicity, as well as antioxidant and glutathione peroxidase (GPx)-like activity. They also regulate antioxidant and pro-inflammatory genes and NRF2 nuclear translocation [19]. Although these studies suggests the cytoprotective properties of 5-HT 6 R ligands, the exact mechanisms associated with the effect remain unclear.…”