Novel 4-Phenylpiperidine-2,6-Dione Derivatives. Ligands for α1-Adrenoceptor Subtypes

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 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 (p K 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.