title: 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 (pK(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.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, viale A. Doria 6, 95125 Catania, Italy. gromeo@unict.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
authors.forename: Luisa
authors.initials: L
authors.lastname: Materia
authors.forename: Maria N
authors.initials: MN
authors.lastname: Modica
authors.forename: Valeria
authors.initials: V
authors.lastname: Pittalà
authors.forename: Loredana
authors.initials: L
authors.lastname: Salerno
authors.forename: Maria A
authors.initials: MA
authors.lastname: Siracusa
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Minneman
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D010881:Piperidones / Q000138:chemical synthesis* / Q000494:pharmacology; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D007295:Inositol Phosphates; D008024:Ligands; D010879:Piperazines; D010881:Piperidones; D020033:Protein Isoforms; D018340:Receptors, Adrenergic, alpha-1; D014316:Tritium; D009638:Norepinephrine