Novel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypes
| Autor: | Kenneth P. Minneman, Maria Angela Siracusa, Maurizio Botta, Loredana Salerno, Luisa Materia, Valeria Pittalà, Fabrizio Manetti, Giuseppe Romeo, Maria N. Modica |
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| Rok vydání: | 2011 |
| Předmět: |
Pharmacology
Chemistry Stereochemistry Organic Chemistry General Medicine Ligands alfa1-Adrenoceptor subtypes 4-Phenylpiperidine-2 Affinities Chemical synthesis 4-Phenylpiperidine-2 6-dione Pharmacophoric model chemistry.chemical_compound Drug Discovery Moiety Inositol Signal transduction Receptor Selectivity Imide α1-Adrenoceptor subtypes 6-dione |
| Zdroj: | European Journal of Medicinal Chemistry. 46:2676-2690 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2011.03.054 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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