Beta-blocking Potency and Selectivity of Bopindolol and Its Two Metabolites for β1-and β2-Adrenergic Receptors as Assessed by Radioligand Binding Assay

Using a radioligand binding assay, we assessed the affinity and selectivity of the antagonistic effects of bopindolol (4-(benzoyloxy-3-tert-butylaminopropyl)-2-methylindole hydrogenmalonate) and its two metabolites, (18-502, (4-(3-tert-butylamino-2-hydroxypropoxy)-2-methyl indole) and 20-785, (4-(3-tert-butylaminopropoxy)-2-carboxyl indole)), for β1-and β2-adrenoceptors and on 5HT1B-receptors in rat brain and heart. In addition, we also determined the pA2 values of these agents for their antagonistic effects toward positive chronotropic and inotropic actions (β1-adrenoceptors) and for their antagonistic effects toward isolated tracheal relaxation (β2-adrenoceptors), using isoproterenol as an agonist. The data showed that bopindolol was more selective for β2-adrenoceptors than for β1-adrenoceptors and 5HT1B-receptors, but its two metabolites (18-502 and 20-785) did not have significant selectivity for β1-and β2-adrenoceptors, using both [3H]CGP12177 and [125I] ICYP ([125I] iodocyanopindolol) bindings. In contrast, the results from pharmacological assessment for antagonistic potencies, using atria and trachea, showed that bopindolol and its two metabolites did not have significant selectivity on β1-and β2-adrenoceptors. A major metabolite of bopindolol, 18-502, had higher pK1 and pA2 values for β-adrenoceptors and 5HT1B-receptors than those of bopindolol and 20-785. These results indicate, first, that a radioligand binding assay for the assessment of the selectivity of bopindolol and its two metabolites for β1-and β2-adrenoceptors is more effective than pharmacological experiments, and that there is a possibility that its two metabolites also contribute to the strong β-blocking action of bopindolol.