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 omega-[4-(substituted phenyl) piperazin-1-yl]alkyl moiety were designed and synthesized as ligands for the alpha(1)-adrenergic receptor (alpha(1)-AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned alpha(1A)-, alpha(1B)-, and alpha(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 alpha(1A)-AR (pK(i) = 8.74) and 10-fold selectivity compared to the other two alpha(1)-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to alpha(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 alpha(1D)-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity alpha(1D)-AR ligands. (C) 2011 Elsevier Masson SAS. All rights reserved.