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Molecules. 2018 Oct 3;23(10). pii: E2529. doi: 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.

Author information

1
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Cracow, Poland. kurczab@if-pan.krakow.pl.
2
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. s8wealii@stud.uni-saarland.de.
3
Division of Bioorganic Chemistry, School of Pharmacy, University of Saarland, Campus B2 1, D-66123 Saarbruecken, D-66123 Saarland, Germany. s8wealii@stud.uni-saarland.de.
4
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. dlazewska@cm-uj.krakow.pl.
5
Department of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. magda.dudek@uj.edu.pl.
6
Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. mj.wiesek@gmail.com.
7
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Cracow, Poland. satala@if-pan.krakow.pl.
8
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. mwiecek@cm-uj.krakow.pl.
9
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. annamaria.lubelska@doctoral.uj.edu.pl.
10
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. glatacz@cm-uj.krakow.pl.
11
Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. annairena.partyka@uj.edu.pl.
12
Department of Inorganic Chemistry, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. m.starek@uj.edu.pl.
13
Department of Inorganic Chemistry, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. monika.1.dabrowska@uj.edu.pl.
14
Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. awesolowska@cm-uj.krakow.pl.
15
Division of Bioorganic Chemistry, School of Pharmacy, University of Saarland, Campus B2 1, D-66123 Saarbruecken, D-66123 Saarland, Germany. c.jacob@mx.uni-saarland.de.
16
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. mfkonono@cyf-kr.edu.pl.
17
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. j.handzlik@uj.edu.pl.

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.

KEYWORDS:

1,3,5-triazine; 5-HT6 ligands; ADMET in vitro; antidepressive; docking; hydantoin; obesity; serotonin receptors

PMID:
30282913
PMCID:
PMC6222450
DOI:
10.3390/molecules23102529
[Indexed for MEDLINE]
Free PMC Article

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