Format

Send to

Choose Destination
Medchemcomm. 2018 May 8;9(6):1033-1044. doi: 10.1039/c8md00168e. eCollection 2018 Jun 1.

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

Author information

1
Department of Technology and Biotechnology of Drugs , Jagiellonian University Medical College , Medyczna 9 , 30-688 Cracow , Poland . Email: jhandzli@cm-uj.krakow.pl ; Tel: +012 620 55 80.
2
Department of Medicinal Chemistry Institute of Pharmacology , Polish Academy of Science , Smętna 12 , 31-343 , Cracow , Poland.
3
Department of Chemistry , Institute of Biology , Pedagogical University of Cracow , Podchorążych 2 , 30-084 Cracow , Poland.
4
Faculty of Chemistry , Jagiellonian University , Gronostajowa 2 , 30-387 , Cracow , Poland.

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).

Supplemental Content

Full text links

Icon for Royal Society of Chemistry Icon for PubMed Central
Loading ...
Support Center