ISSN:
1432-1912
Schlagwort(e):
β-Adrenoceptor antagonists
;
β-Adrenoceptor subtypes
;
Competition binding studies
;
[3H]CGP-12177
;
Subtype selectivity
Quelle:
Springer Online Journal Archives 1860-2000
Thema:
Medizin
Notizen:
Summary On the basis of saturation binding studies on rat cardiac microsomes, which contained a mixed population of β-adrenoceptor subtypes, [3H]CGP-12177 is presumed to be a non-selective β-adrenergic radioligand. However, saturation binding studies carried out in the presence of subtype-saturating concentrations of the β2-selective antagonist ICI 118,551 and the β1-selective antagonist ICI 89,406, respectively, revealed a K D for β1-adrenoceptors of 0.33 ± 0.02 nmol/l and a K D for β2-adrenoceptors of 0.90 ± 0.14 nmol/l. Competition experiments with the highly selective antagonists revealed greatly different competition binding curves in the presence of either [3H]CGP-12177 or (−)[125I]iodocyanopindolol (ICYP), a β-adrenergic radioligand considered to be as non-selective as [3H]CGP-12177. The following results are further suggestive for a selectivity of [3H]CGP-12177 for β1-adrenoceptors: (1) Using non-linear regression analysis, a significantly lower selectivity (expressed as the ratio of the IC50 for β2-adrenoceptors to the IC50 for β1-adrenoceptors) as well as a larger proportion of β1-adrenoceptors were calculated by competition of the β1-selective antagonist ICI 89,406 with [3H]CGP-12177 binding than by competition of ICI 89,406 with ICYP binding; (2) reducing the [3H]CGP-12177 concentration from 2 to 0.4 nmol/l, competition experiments with ICI 89,406 led to an increase in the estimated selectivity of the competitor and in the estimated proportion of β1-adrenoceptors; (3) reverse findings were obtained with ICI 118,551, a β2-selective antagonist. Theoretical competition data assuming a varying selectivity of the radioligand were generated using an equation which describes inhibition of the binding of a selective radioligand by a selective competing ligand. Analysis of these data by the model which assumes that the radioligand is entirely non-selective revealed a logarithmic relationship between the distortion of the true selectivity of the competing ligand and the degree of selectivity of the radioligand. For instance, the selectivity of ICI 89,406, estimated against [3H]CGP-12177 binding, was 23% of its selectivity estimated against ICYP binding. Hence, non-linear fits of competition curves with subtype-selective unlabeled ligands will result in serious distortion in the estimates of affinity of the competing ligands and in the size of subtype populations if [3H]CGP-12177 is considered entirely non-selective.
Materialart:
Digitale Medien
URL:
http://dx.doi.org/10.1007/BF00169308
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