The role of a low β1-adrenoceptor selectivity of [3H]CGP-12177 for resolving subtype-selectivity of competitive ligands

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