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    Novel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypes

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    Type
    Article
    Authors
    Romeo, Giuseppe F.
    Materia, Luisa
    Modica, Maria Nunziata
    Pittal, Valeria
    Salerno, Loredana
    Siracusa, Maria Angela
    Manetti, Fabrizio
    Botta, Maurizio
    Minneman, Kenneth P.
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Date
    2011-07
    Permanent link to this record
    http://hdl.handle.net/10754/561806
    
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    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 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.2011.03.054
    Publisher
    Elsevier BV
    Journal
    European Journal of Medicinal Chemistry
    DOI
    10.1016/j.ejmech.2011.03.054
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ejmech.2011.03.054
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division

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