Abstract
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-HT1A, 5-HT2A, 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 (18 and 26) were identified as the most active 5-HT6R agents within each lead modification line, respectively. The 5-(2-naphthyl)hydantoin derivative 26, the most active one in the series (5-HT6R: Ki = 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 18 and 26, respectively. Compound 26 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.
Highlights
The serotonin receptor 5-HT6 is one of the recently discovered members of the 5-HTRs family [1].The serotonin receptor 5-HT6 is one of the recently discovered members of the 5-HTRs familyIt is quite unique, since it includes a short third cytoplasmatic loop in parallel, with a long C-terminal [1]
Is limited to the central nervous system, especially as it is located in the areas localization of 5-HT6R is limited to the central nervous system, especially as it is located in brain the brain involved in learning and memory processes
Four different hydantoin moieties were taken into consideration lead structure
Summary
The serotonin receptor 5-HT6 is one of the recently discovered members of the 5-HTRs family [1].The serotonin receptor 5-HT6 is one of the recently discovered members of the 5-HTRs familyIt is quite unique, since it includes a short third cytoplasmatic loop in parallel, with a long C-terminal [1]. The serotonin receptor 5-HT6 is one of the recently discovered members of the 5-HTRs family. It is quite unique, since it includes a short third cytoplasmatic loop in parallel, with a long C-terminal [1]. R is limited to the central nervous system, especially as it is located in the areas localization of 5-HT6R is limited to the central nervous system, especially as it is located in brain the brain involved in learning and memory processes. Limited, but intensive, research efforts in areas involved in learning and memory processes. Alzheimer’s anxiety or depression potential treatment in the cognitiveassociated dysfunction associated withdisease, Alzheimer’s disease, anxiety [5,6,7]
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