Computer-Aided Studies for Novel Arylhydantoin 1,3,5-Triazine Derivatives As 5-HT₆ Serotonin Receptor Ligands with Antidepressive-Like, Anxiolytic and Antiobesity Action In Vivo

This study focuses on the design, synthesis, biological evaluation, and computer-aided structure-activity relationship (SAR) analysis for a novel group of aromatic triazine-methylpiperazines, with an hydantoin spacer between 1,3,5-traizine and the aromatic fragment. New compounds were synthesized and their affinities for serotonin 5-HT₆, 5-HT, 5-HT, 5-HT₇, and dopamine D₂ receptors were evaluated. The induced-fit docking (IFD) procedure was performed to explore the 5-HT₆ receptor conformation space employing two lead structures. It resulted in a consistent binding mode with the activity data. For the most active compounds found in each modification line, anti-obesity and anti-depressive-like activity in vivo, as well as "druglikeness" in vitro, were examined. Two 2-naphthyl compounds ( and ) were identified as the most active 5-HT₆R agents within each lead modification line, respectively. The 5-(2-naphthyl)hydantoin derivative , the most active one in the series (5-HT₆R: = 87 nM), displayed also significant selectivity towards competitive G-protein coupled receptors (6⁻197-fold). Docking studies indicated that the hydantoin ring is stabilized by hydrogen bonding, but due to its different orientation, the hydrogen bonds form with S5.44 and N6.55 or Q6.58 for and , respectively. Compound exerted anxiolytic-like and antidepressant-like activities. Importantly, it demonstrated anti-obesity properties in animals fed palatable feed, and did not show toxic effects in vitro.