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

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 (pKi = 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.

A series of new 4-phenylpiperidine-2,6-diones were prepared and evaluated for their affinities at the three α1-adrenoceptor subtypes. Binding data were used for the refinement of a pharmacophoric model for α1D-adrenoceptors.Figure optionsDownload as PowerPoint slideHighlights
► New 4-phenylpiperidine-2,6-diones as ligands for the α1-adrenoceptor subtypes.
► Receptor affinity was strongly influenced by the length of alkyl connecting chain.
► Highest affinity values were found in compounds with a butyl connecting chain.
► New derivatives behaved as α1-adrenoceptor antagonists in a functional assay.
► A refined pharmacophoric model for α1D-adrenoceptors was developed.