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Eur J Med Chem. 2018 Mar 10;147:102-114. doi: 10.1016/j.ejmech.2018.01.093. Epub 2018 Feb 1.

Computer-aided insights into receptor-ligand interaction for novel 5-arylhydantoin derivatives as serotonin 5-HT7 receptor agents with antidepressant activity.

Author information

1
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
2
Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Cracow, Poland.
3
Department of Clinical Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
4
Department of Chemistry, Institute of Biology, Pedagogical University of Cracow, Podchorążych 2, 30-084 Cracow, Poland.
5
Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.
6
Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
7
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland. Electronic address: jhandzli@cm-uj.krakow.pl.

Abstract

This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (1, MF-8), as part of the search for potent and selective serotonin 5-HT7 receptor (5-HT7R) agents. New hydantoin derivatives (4-19) were designed and synthesized. For 5-phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (4), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT7R and selectivity over 5-HT1AR, dopamine D2R and α1-, α2-and β-adrenoceptors. Selected compounds (5-8) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT7R in RBA, in particular seven compounds (4, 5, 7, 8 and 10-12,Ki ≤ 10 nM). Antidepressant-like activity in vivo for all tested compounds (5-8) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono-phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT7R affinity than the di-phenyl ones.

KEYWORDS:

5-HT(7)R ligands; Antidepressant; Arylpiperazine; CNS drugability; Docking; Hydantoin; Serotonin receptors

PMID:
29425815
DOI:
10.1016/j.ejmech.2018.01.093
[Indexed for MEDLINE]

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