Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/5935
Title: Novel 4-Phenylpiperidine-2,6-Dione Derivatives. Ligands for α1-Adrenoceptor Subtypes
Authors: Romeo, G
Materia, L
MODICA M., N
Pittalà, V
Salerno, L
SIRACUSA M., A
Manetti, Fabrizio 
Botta, Maurizio 
Minneman, K. P.
Keywords: α1-Adrenoceptor subtypes; 4-Phenylpiperidine-2; 6-dione; Ligands; Pharmacophoric model
Issue Date: 2011
Project: None 
Journal: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Abstract: 
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.
Description: 
25297
URI: http://hdl.handle.net/20.500.12779/5935
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2011.03.054
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