SAR-studies on the importance of aromatic ring topologies in search for selective 5-HT7 receptor ligands among phenylpiperazine hydantoin derivatives

Jadwiga Handzlik, Andrzej J. Bojarski, Grzegorz Satała, Monika Kubacka, Bassem Sadek, Abrar Ashoor, Agata Siwek, Małgorzata Wiȩcek, Katarzyna Kucwaj, Barbara Filipek, Katarzyna Kieć-Kononowicz

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29 Citations (Scopus)

Abstract

The current study is focused on newly developed phenylpiperazine derivatives of aromatic methylhydantoin differing in mutual positions of methyl and phenyl moieties. The new compounds were synthesized using Bucherer-Bergs reaction, two-phase alkylation, Mitsunobu reaction and/or an alkylation under microwave irradiation. The compounds developed were assessed on their affinity for serotoninergic receptors 5-HT1A, 5-HT6, 5-HT 7 and α1-ARs in radioligand binding assays. Selected compounds were tested on their inhibitory effect at human 5-HT3A expressed in Xenopus Oocytes as well as on their activity at α1-adrenoceptor subtypes in functional and electrophysiological bioassays, respectively. Most of investigated compounds exhibited affinities for α1-ARs, 5-HT1A, 5-HT7 (Ki ∼ 0.8-353 nM) significantly higher than those for 5-HT6 receptors. Very weak inhibitory effect at 5-HT3A accompanied with high activity at α1D-AR subtypes were observed for selected representative compounds. Among the current series, particularly 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl) -5-methylimidazolidine-2,4-dione hydrochloride (25a) displayed the highest 5-HT7 affinity with Ki = 3 nM and selectivity with 40-3600 fold towards 5-HT1A, 5-HT6, and α1-ARs.

Original languageEnglish
Pages (from-to)324-339
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume78
DOIs
Publication statusPublished - May 6 2014

Keywords

  • Alpha1-adrenoceptor
  • Hydantoins
  • Mitsunobu reaction
  • Phenylpiperazines

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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