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Molecules 2018, 23(10), 2529; https://doi.org/10.3390/molecules23102529

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

1
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Cracow, Poland
2
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland
3
Division of Bioorganic Chemistry, School of Pharmacy, University of Saarland, Campus B2 1, D-66123 Saarbruecken, D-66123 Saarland, Germany
4
Department of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland
5
Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland
6
Department of Inorganic Chemistry, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 1 September 2018 / Revised: 22 September 2018 / Accepted: 24 September 2018 / Published: 3 October 2018
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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. View Full-Text
Keywords: serotonin receptors; 5-HT6 ligands; 1,3,5-triazine; hydantoin; docking; obesity; antidepressive; ADMET in vitro serotonin receptors; 5-HT6 ligands; 1,3,5-triazine; hydantoin; docking; obesity; antidepressive; ADMET in vitro
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Kurczab, R.; Ali, W.; Łażewska, D.; Kotańska, M.; Jastrzębska-Więsek, M.; Satała, G.; Więcek, M.; Lubelska, A.; Latacz, G.; Partyka, A.; Starek, M.; Dąbrowska, M.; Wesołowska, A.; Jacob, C.; Kieć-Kononowicz, K.; Handzlik, J. 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. Molecules 2018, 23, 2529.

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