Novel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypes
Type
ArticleAuthors
Romeo, Giuseppe F.Materia, Luisa
Modica, Maria Nunziata
Pittal, Valeria
Salerno, Loredana
Siracusa, Maria Angela
Manetti, Fabrizio
Botta, Maurizio
Minneman, Kenneth P.
Date
2011-07Permanent link to this record
http://hdl.handle.net/10754/561806
Metadata
Show full item recordAbstract
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 (pK i = 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. © 2011 Elsevier Masson SAS. All rights reserved.Citation
Romeo, G., Materia, L., Modica, M. N., Pittalà, V., Salerno, L., Siracusa, M. A., … Minneman, K. P. (2011). Novel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypes. European Journal of Medicinal Chemistry, 46(7), 2676–2690. doi:10.1016/j.ejmech.2011.03.054Publisher
Elsevier BVae974a485f413a2113503eed53cd6c53
10.1016/j.ejmech.2011.03.054