Sakuma N, Tsuchihashi H, Hosohata Y, Akashi H, Kinami J, Nagatomo T
Department of Pharmacology, Niigata College of Pharmacy, Japan.
J Pharmacobiodyn. 1991 May;14(5):250-5. doi: 10.1248/bpb1978.14.250.
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.
我们采用放射性配体结合试验，评估了波吲洛尔（4-(苯甲酰氧基-3-叔丁氨基丙基)-2-甲基吲哚氢丙二酸酯）及其两种代谢产物（18 - 502，即4-(3-叔丁氨基-2-羟基丙氧基)-2-甲基吲哚；以及20 - 785，即4-(3-叔丁氨基丙氧基)-2-羧基吲哚）对大鼠脑和心脏中β1和β2肾上腺素能受体以及5HT1B受体的拮抗作用的亲和力和选择性。此外，我们还以异丙肾上腺素为激动剂，测定了这些药物对正性变时和变力作用（β1肾上腺素能受体）的拮抗作用以及对离体气管舒张（β2肾上腺素能受体）的拮抗作用的pA2值。数据表明，使用[3H]CGP12177和[125I]ICYP（[125I]碘氰吲哚洛尔）结合试验时，波吲洛尔对β2肾上腺素能受体的选择性高于对β1肾上腺素能受体和5HT1B受体，但它的两种代谢产物（18 - 502和20 - 785）对β1和β2肾上腺素能受体没有显著的选择性。相比之下，使用心房和气管进行的拮抗效力药理学评估结果显示，波吲洛尔及其两种代谢产物对β1和β2肾上腺素能受体没有显著的选择性。波吲洛尔的主要代谢产物18 - 502对β肾上腺素能受体和5HT1B受体的pKi和pA2值高于波吲洛尔和20 - 785。这些结果首先表明，用于评估波吲洛尔及其两种代谢产物对β1和β2肾上腺素能受体选择性的放射性配体结合试验比药理学实验更有效，并且其两种代谢产物也有可能对波吲洛尔强大的β受体阻滞作用有贡献。
