Ligand modulation of [35S]GTPgammaS binding at human alpha(2A), alpha(2B) and alpha(2C) adrenoceptors.
Affinities and efficacies of chemically diverse ligands--some of them used as clinical agents--were examined, employing [3H]RX821,002 and [35S]GTPgammaS binding assays, respectively, at human (h) cloned, halpha(2A), halpha(2B) and halpha(2C) adrenoceptors (AR) expressed in Chinese hamster ovary (CHO) cells. As compared to noradrenaline (NA, efficacy defined as 100%), the majority of the 13 agonists tested generally behaved as partial agonists. Amongst 18 antagonists, pK(B) and pK(i) values, which were highly correlated for each alpha(2)-AR subtype, failed to reveal any strikingly selective agents. Inverse agonist properties were not detected for any antagonist, consistent with a lack of constitutive activity suggested by the monophasic inhibition of [35S]GTPgammaS binding by GTPgammaS. These data should facilitate interpretation of experimental and clinical actions of adrenergic agonists. Moreover, they emphasize the continuing need for alpha(2)-AR subtype-selective antagonists in order to define further the roles and therapeutic relevance of halpha(2A)-, halpha(2B)-, and halpha(2C)-AR.
Audinot
Valérie
V
Département de Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 125, Chemin de Ronde, 78290 Croissy-sur-Seine, France. valerie.audinot@fr.netgrs.com
Fabry
Nelly
N
Nicolas
Jean-Paul
JP
Beauverger
Philippe
P
Newman-Tancredi
Adrian
A
Millan
Mark J
MJ
Try
Anne
A
Bornancin
Frédéric
F
Canet
Emmanuel
E
Boutin
Jean A
JA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006801:Humans; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012965:Sodium Chloride / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D014162:Transfection
C547768:ADRA2A protein, human; C547771:ADRA2B protein, human; C547774:ADRA2C protein, human; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D012965:Sodium Chloride; D009638:Norepinephrine