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

Abstract

In order to search for active and selective serotonin 5-HT7¬R antagonists among 3,5-disubstituted arylpiperazine-imidazolidine-2,4-diones, the role of introduction/deletion and mutual orientation of aromatic rings was analyzed. Chemical modifications of 2nd generation lead structure, 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. The X-ray crystallographic analysis for 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 the radioligand binding assays for whole series and ADME-Tox parameters in vitro for selected compounds (7, 10, 13), were evaluated. The molecular docking and pharmacophore model assessment were performed. As results, 5-methyl-5-naphtylhydantoin derivatives were found as new highly active 5-HT7R agents (Ki ≤ 5 nM) with significant selectivity over 5-HT1AR and D2R. In contrary, the (1-naphthyl)piperazine moiety gained with the potent dual 5-HT7R/5-HT1AR action (Ki: 11 nM/19 nM).

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Supplementary files

Publication details

The article was received on 27 Mar 2018, accepted on 04 May 2018 and first published on 08 May 2018


Article type: Research Article
DOI: 10.1039/C8MD00168E
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    The role of aryl-topology for balancing between selective and dual 5-HT7R/5-HT1A action of 3,5-substituted hydantoins

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

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