Novel 4-phenylpiperidine-2,6-dione Derivatives. Ligands for α₁-adrenoceptor Subtypes

Eur J Med Chem. 2011 Jul;46(7):2676-90. doi: 10.1016/j.ejmech.2011.03.054. Epub 2011 Apr 3.


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 α(1)-adrenergic receptor (α(1)-AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned α(1A)-, α(1B)-, and α(1D)-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 α(1A)-AR (pK(i) = 8.74) and 10-fold selectivity compared to the other two α(1)-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to α(1)-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 α(1D)-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity α(1D)-AR ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists / chemical synthesis*
  • Adrenergic alpha-1 Receptor Antagonists / pharmacology
  • HEK293 Cells
  • Humans
  • Hydrolysis
  • Inositol Phosphates / metabolism
  • Ligands
  • Norepinephrine / antagonists & inhibitors
  • Norepinephrine / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology
  • Piperidones / chemical synthesis*
  • Piperidones / pharmacology
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Radioligand Assay
  • Receptors, Adrenergic, alpha-1 / chemistry*
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • Tritium


  • Adrenergic alpha-1 Receptor Antagonists
  • Inositol Phosphates
  • Ligands
  • Piperazines
  • Piperidones
  • Protein Isoforms
  • Receptors, Adrenergic, alpha-1
  • Tritium
  • Norepinephrine