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A number of new 4-phenylpiperidine-2,6-diones bearing at the 1-position an omega-[4-(substituted phenyl) piperazin-1-yl]alkyl moiety were designed and synthesized as ligands for the alfa1-adrenergic receptor (alfa1-AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned alfa1A-, alfa1B-, and alfa1D-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 alfa1A-AR (pKi = 8.74) and 10-fold selectivity compared to the other two alfa1-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to alfa1-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 alfa1D-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity alfa1D-AR ligands.

A number of new 4-phenylpiperidine-2,6-diones bearing at the 1-position an omega-[4-(substituted phenyl) piperazin-1-yl]alkyl moiety were designed and synthesized as ligands for the alpha1-adrenergic receptor (alpha1- AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned alpha1A-, alpha1B-, and alpha1D-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 alpha1A-AR (pKi = 8.74) and 10-fold selectivity compared to the other two alpha1-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to alpha1-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 alpha1D-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity alpha1D-AR ligands.

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