Novel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypes

Giuseppe F. Romeo, Luisa Materia, Maria Nunziata Modica, Valeria Pittal, Loredana Salerno, Maria Angela Siracusa, Fabrizio Manetti, Maurizio Botta, Kenneth P. Minneman

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


A number of new 4-phenylpiperidine-2,6-diones bearing at the 1-position an ω-[4-(substituted phenyl)piperazin-1-yl]alkyl moiety were designed and synthesized as ligands for the α1-adrenergic receptor (α1-AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned α1A-, α1B-, and α1D-AR subtypes, displayed affinities in the nanomolar range. Highest affinity values were found in derivatives having a butyl connecting chain between the 4-phenylpiperidine-2,6-dione and the phenylpiperazinyl moieties. 1-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl]-4-phenylpiperidine-2,6- dione (34) showed the best affinity for the α1A-AR (pK i = 8.74) and 10-fold selectivity compared to the other two α1-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to α1-AR subtypes. They all blocked norepinephrine-induced stimulation of inositol phospholipid hydrolysis, thus behaving as antagonists. Binding data were used to refine a previously developed pharmacophoric model for α1D-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity α1D-AR ligands. © 2011 Elsevier Masson SAS. All rights reserved.
Original languageEnglish (US)
Pages (from-to)2676-2690
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Issue number7
StatePublished - Jul 2011

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Pharmacology


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