Beta-blocking potency and selectivity of bopindolol and its two metabolites for beta 1- and beta 2-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 hydrogen-malonate) 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 beta 1- and beta 2-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 (beta 1-adrenoceptors) and for their antagonistic effects toward isolated tracheal relaxation (beta 2-adrenoceptors), using isoproterenol as an agonist. The data showed that bopindolol was more selective for beta 2-adrenoceptors than for beta 1-adrenoceptors and 5HT1B-receptors, but its two metabolites (18-502 and 20-785) did not have significant selectivity for beta 1- and beta 2-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 beta 1- and beta 2-adrenoceptors. A major metabolite of bopindolol, 18-502, had higher pKi and pA2 values for beta-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 beta 1- and beta 2-adrenoceptors is more effective than pharmacological experiments, and that there is a possibility that its two metabolites also contribute to the strong beta-blocking action of bopindolol.
Sakuma
N
N
Department of Pharmacology, Niigata College of Pharmacy, Japan.
Tsuchihashi
H
H
Hosohata
Y
Y
Akashi
H
H
Kinami
J
J
Nagatomo
T
T
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D020120:Iodocyanopindolol; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010869:Pindolol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011412:Propanolamines; D011869:Radioligand Assay; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D014132:Trachea / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C038186:4-(2-hydroxy-3-tert-butylaminopropoxy)-2-methylindole; C061293:4-(3-tert-butylamino-2-hydroxypropoxy)-2-carboxyindole; D020120:Iodocyanopindolol; D010869:Pindolol; C036007:bopindolol; C033394:CGP 12177