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Eur J Med Chem. 2016 Apr 13;112:258-269. doi: 10.1016/j.ejmech.2016.02.024. Epub 2016 Feb 9.

Rational design in search for 5-phenylhydantoin selective 5-HT7R antagonists. Molecular modeling, synthesis and biological evaluation.

Author information

1
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
2
Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
3
Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland; Faculty of Chemistry, Jagiellonian University, Ingardena 3, PL 30-060, Kraków, Poland.
4
Department of Pharmacology, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Spain.
5
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: j.handzlik@uj.edu.pl.

Abstract

A series of novel arylpiperazine 5-(4-fluorophenyl)-5-methylhydantoins with 2-hydroxypropyl linker (2-15) was synthesized and evaluated on their affinity towards serotonin 5-HT7 receptor (5-HT7R) in comparison to other closely related GPCRs: serotonin 5-HT1A, and dopamine D2 receptors. The functional activity studied through the measurement of 5-HT7R-mediated cyclic AMP production in Human Embryonic Kidney 293 cells (HEK293) stably expressing human 5-HT7 proved their antagonistic properties. The lead structure was also examined in the preliminary metabolic stability study using human liver microsomes (HMLs). The process of selection of candidates for synthesis was supported by a special molecular modeling workflow including combinatorial library generation, docking, and machine learning-based assessment. Additionally, in silico predictions of selectivity over 5-HT1AR and D2R, as well as functional activity were carried out. The newly synthesized compounds were proved to possess a potent affinity for 5-HT7R, similar to that of the lead structure of 5-(4-fluorophenyl)-3-(3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)-5-methylimidazolidine-2,4-dione (1). For several derivatives, significant selectivity both over 5-HT1AR and D2R was found.

KEYWORDS:

5-HT(1A)R; 5-HT(7)R; 5-HT(7)R antagonists; D(2)R; Hydantoins; Phenylpiperazines; Virtual screening

PMID:
26900658
DOI:
10.1016/j.ejmech.2016.02.024
[Indexed for MEDLINE]

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