A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.

Détails

ID Serval
serval:BIB_766ECE57D25B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.
Périodique
Naunyn-schmiedeberg's Archives of Pharmacology
Auteur(s)
Hein P., Goepel M., Cotecchia S., Michel M.C.
ISSN
0028-1298 (Print)
ISSN-L
0028-1298
Statut éditorial
Publié
Date de publication
2001
Volume
363
Numéro
1
Pages
34-39
Langue
anglais
Résumé
In order to characterize inverse agonism at alpha1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline alpha1-adrenoceptor antagonists at cloned hamster wild-type (WT) alpha1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline alpha1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with Ki values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was approximately 55%, and the corresponding EC50 values were slightly smaller than the Ki values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that alpha1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without.
Mots-clé
Adrenergic alpha-1 Receptor Agonists, Adrenergic alpha-1 Receptor Antagonists, Adrenergic alpha-Antagonists/pharmacology, Animals, Cell Line, Chromones/pharmacology, Cricetinae, Dose-Response Relationship, Drug, Doxazosin/pharmacology, Fibroblasts/cytology, Fibroblasts/drug effects, Inositol Phosphates/metabolism, Phenethylamines/pharmacology, Prazosin/analogs & derivatives, Prazosin/pharmacology, Quinazolines/pharmacology, Rats, Receptors, Adrenergic, alpha-1/genetics, Sulfonamides/pharmacology, Tetralones, Tritium/diagnostic use
Pubmed
Web of science
Création de la notice
24/01/2008 11:05
Dernière modification de la notice
20/08/2019 14:33
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