Please use this identifier to cite or link to this item: doi:10.22028/D291-27518
Title: 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
Author(s): Kurczab, Rafał
Ali, Wesam
Łażewska, Dorota
Kotańska, Magdalena
Jastrzębska-Więsek, Magdalena
Satała, Grzegorz
Więcek, Małgorzata
Lubelska, Annamaria
Latacz, Gniewomir
Partyka, Anna
Starek, Małgorzata
Dąbrowska, Monika
Wesołowska, Anna
Jacob, Claus
Kieć-Kononowicz, Katarzyna
Handzlik, Jadwiga
Language: English
Title: Molecules
Volume: 23
Issue: 10
Publisher/Platform: MDPI
Year of Publication: 2018
Free key words: serotonin receptors
5-HT6 ligands
1,3,5-triazine
hydantoin
docking
obesity
antidepressive
ADMET in vitro
DDC notations: 540 Chemistry
Publikation type: Journal Article
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.
DOI of the first publication: 10.3390/molecules23102529
Link to this record: urn:nbn:de:bsz:291--ds-275185
hdl:20.500.11880/28905
http://dx.doi.org/10.22028/D291-27518
ISSN: 1420-3049
Date of registration: 22-Mar-2020
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Pharmazie
Professorship: NT - Prof. Dr. Claus Jacob
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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