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Issue 6, 2018
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The role of aryl-topology in balancing between selective and dual 5-HT7R/5-HT1A actions of 3,5-substituted hydantoins

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Abstract

In order to search for active and selective serotonin 5-HT7R antagonists among 3,5-disubstituted arylpiperazine-imidazolidine-2,4-diones, the role of the introduction/deletion and the mutual orientation of aromatic rings was analyzed. Chemical modifications of 2nd generation lead structure of 3-(3-(4-(diphenylmethyl)piperazin-1-yl)-2-hydroxypropyl)-5-(4-fluorophenyl)-5-methylimidazolidine-2,4-dione (2, KKB16) were performed. New derivatives (4–18) were designed and synthesized. X-ray crystallographic analysis of the representative compound 5-(4-fluorophenyl)-3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl]-5-methylimidazolidine-2,4-dione (3) was performed to support molecular modeling and SAR studies. The affinity for 5-HT7R, D2R and 5-HT1AR in radioligand binding assays for the entire series and ADME-Tox parameters in vitro for selected compounds (7, 10, and 13) were evaluated. Molecular docking and pharmacophore model assessment were performed. According to the obtained results, 5-methyl-5-naphthylhydantoin derivatives were found to be the new highly active 5-HT7R agents (Ki ≤ 5 nM) with significant selectivity over 5-HT1AR and D2R. On the contrary, the (1-naphthyl)piperazine moiety was gained with the potent dual 5-HT7R/5-HT1AR action (Ki: 11 nM/19 nM).

Graphical abstract: The role of aryl-topology in balancing between selective and dual 5-HT7R/5-HT1A actions of 3,5-substituted hydantoins

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Supplementary files

Article information


Submitted
27 Mar 2018
Accepted
04 May 2018
First published
08 May 2018

Med. Chem. Commun., 2018,9, 1033-1044
Article type
Research Article

The role of aryl-topology in balancing between selective and dual 5-HT7R/5-HT1A actions of 3,5-substituted hydantoins

K. Kucwaj-Brysz, R. Kurczab, E. Żesławska, A. Lubelska, M. A. Marć, G. Latacz, G. Satała, W. Nitek, K. Kieć-Kononowicz and J. Handzlik, Med. Chem. Commun., 2018, 9, 1033
DOI: 10.1039/C8MD00168E

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