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Rational Design in Search for 5-phenylhydantoin Selective 5-HT7R Antagonists. Molecular Modeling, Synthesis and Biological Evaluation

Rational Design in Search for 5-phenylhydantoin Selective 5-HT7R Antagonists. Molecular Modeling, Synthesis and Biological Evaluation

Katarzyna Kucwaj-Brysz, Dawid Warszycki, Sabina Podlewska, Jagna Witek, Karolina Witek, Andrea González Izquierdo, Grzegorz Satała, María I Loza, Annamaria Lubelska, Gniewomir Latacz, Andrzej J Bojarski, etc.

Eur J Med Chem. 2016 Apr 13;112:258-269.

PMID: 26900658

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP89247	5-Phenylhydantoin		89-24-7	Price

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