Inverse agonism and neutral antagonism at alpha(1a)- and alpha(1b)-adrenergic receptor subtypes.

Détails

ID Serval
serval:BIB_483FB610FCC9
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Inverse agonism and neutral antagonism at alpha(1a)- and alpha(1b)-adrenergic receptor subtypes.
Périodique
Molecular Pharmacology
Auteur(s)
Rossier O., Abuin L., Fanelli F., Leonardi A., Cotecchia S.
ISSN
0026-895X (Print)
ISSN-L
0026-895X
Statut éditorial
Publié
Date de publication
1999
Volume
56
Numéro
5
Pages
858-866
Langue
anglais
Résumé
We have characterized the pharmacological antagonism, i.e., neutral antagonism or inverse agonism, displayed by a number of alpha-blockers at two alpha1-adrenergic receptor (AR) subtypes, alpha(1a)- and alpha(1b)-AR. Constitutively activating mutations were introduced into the alpha(1a)-AR at the position homologous to A293 of the alpha(1b)-AR where activating mutations were previously described. Twenty-four alpha-blockers differing in their chemical structures were initially tested for their effect on the agonist-independent inositol phosphate response mediated by the constitutively active A271E and A293E mutants expressed in COS-7 cells. A selected number of drugs also were tested for their effect on the small, but measurable spontaneous activity of the wild-type alpha(1a)- and alpha(1b)-AR expressed in COS-7 cells. The results of our study demonstrate that a large number of structurally different alpha-blockers display profound negative efficacy at both the alpha(1a)- and alpha(1b)-AR subtypes. For other drugs, the negative efficacy varied at the different constitutively active mutants. The most striking difference concerns a group of N-arylpiperazines, including 8-[2-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4, 5] decane-7,9-dione (REC 15/3039), REC 15/2739, and REC 15/3011, which are inverse agonists with profound negative efficacy at the wild-type alpha(1b)-AR, but not at the alpha(1a)-AR.
Mots-clé
Adrenergic alpha-1 Receptor Antagonists, Adrenergic alpha-Antagonists/pharmacology, Animals, COS Cells, Cricetinae, Humans, Inositol Phosphates/metabolism, Ligands, Models, Molecular, Mutagenesis, Receptors, Adrenergic, alpha-1/genetics, Structure-Activity Relationship, Transfection
Pubmed
Web of science
Création de la notice
24/01/2008 11:05
Dernière modification de la notice
20/08/2019 13:55
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