Beta-blocking Potency and Selectivity of Bopindolol an Its Two Metabolites for .BETA.1- and .BETA.2-Adrenergic Receptors as Assessed by Radioligand Binding Assay.

Sakuma, Noriko; Tsuchihashi, Hiroshi; Hosohata, Yoshiaki; Akashi, Hirofumi; Kinami, Junji; Nagatomo, Takafumi

doi:10.1248/bpb1978.14.250

Cited by 10 publications

(14 citation statements)

References 17 publications

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“…Several previous reports have indicated (1) the slowly reversible nature of binding of bopindolol to receptors [10]; (2) the presence of active metabolites [11]; (3) the shallow slope of the plasma concentration-effect relationship [12,13], and (4) the small dissociation Hosohata/Hattori/Shen/Okuyama/ Kaneko/Ohnuki/Suzuki/Nagatomo constant of the drug-receptor complex [14]. Our previous study [2] also showed a slow dissociation of bopindolol and metabolite 18-502 from ß-ARs in the rat and guinea pig heart using pharmacological methods and the radioligand-binding assay.…”

Section: Discussionmentioning

confidence: 94%

“…We have previously demonstrated that bopindolol, which is a prodrug, acted as a nonselective ß-blocker [1], showed slow dissociation from ß-ARs in rat and guinea pig hearts [2], and exhibited partial agonist activity [5]. There is increasing evidence that bopindolol possesses long-acting ß-blocking action with high affinity and partial agonist activity to the ß-ARs in both healthy volunteers and animal models [9,11,13,14], suggesting that less frequent administration may be necessary than with most other ß-blockers [6,7,11].…”

Section: Discussionmentioning

confidence: 99%

“…Strips of left atria were obtained from male guinea pigs, weighing 300-400 g, as described previously [1]. Briefly, to evaluate the inotropic effects, the left atrium was stimulated electrically by a square wave stimulator (Nihon Koden SEN-3101) at a frequency of 1 Hz, with voltages 30% above the threshold.…”

Section: Pharmacological Experimentsmentioning

confidence: 99%

“…Our previous studies [1][2][3][4][5] using radioligand-binding assay and pharmacological experiments showed that a nonselective adrenoceptor (AR) antagonist ß-blocker, bopindolol, is a long-acting drug, implying that this drug dissociates slowly from ß-ARs. This may explain its long-lasting antihypertensive effects.…”

Section: Introductionmentioning

confidence: 99%

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Bopindolol: A Slowly Dissociating Antagonist from the β-Adrenoceptors in Guinea Pig Atria

Hosohata

Hattori²,

Shen³

et al. 1998

Pharmacology

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The dissociating and/or residual inhibitory effects of bopindolol from β-adrenoceptors of atria strips pretreated with this drug which was then washed out with buffers on the responses to isoprenaline were determined and compared with those of propranolol, pindolol, atenolol, and the two active metabolites of bopindolol: 18-502 and 20-785. Low concentrations of bopindolol (10^–9 to 10^–8 mol/l) and the active metabolite 18-502 (10^–9 mol/l) produced rightward shifts of the concentration-response curves. On the other hand, high concentrations of bopindolol (10^–7 mol/l) and metabolite 18-502 (10^–8 and 10^–7 mol/l) produced a reduced maximum response by isoprenaline, suggesting that these nonparallel rightward shifts have pD₂ values of 7.57 (bopindolol) and 7.67 (18-502), respectively, at 0 min after washout with buffers. Pindolol (10^–7 mol/l) and propranolol (10^–7 and 10^–8 mol/l) also produced a rightward shift of isoprenaline response curves, and these concentration-response curves in guinea pig atria strips pretreated with pindolol (10^–7 mol/l) and propranolol (10^–6 mol/l) recovered to control levels. Neither of these drugs, however, reduced the maximum response by isoprenaline. A high concentration (10^–5 mol/l) of atenolol was required for a rightward shift of the isoprenaline concentration-response curve, and this drug also did not reduce the maximum response. Thus, we conclude that bopindolol and metabolite 18-502 slowly dissociate and act as noncompetitive β-antagonists rather than easily reversible β-adrenoceptor antagonists.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Pharmacological Experimentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Bopindolol: A Slowly Dissociating Antagonist from the β-Adrenoceptors in Guinea Pig Atria

Hosohata

Hattori²,

Shen³

et al. 1998

Pharmacology

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“…In the case of 20-785, the methyl group on the indole ring is oxidized to carboxylic acid. Binding studies of bopindolol and the two metabolites suggested that the different functional groups of these compounds may be responsible for the different binding affinities of each ligand at the ß 1 -AR [7,8]. Thus, it would be of interest to assess the interactions between chemical structures of these compounds and amino acids of ß 1 -ARs at the molecular level using molecular modeling.…”

Section: Introductionmentioning

confidence: 99%

Identification of Binding Sites of Bopindolol and Its Two Metabolites with β<sub>1</sub>-Adrenoceptors by Molecular Modeling: Comparison with β<sub>2</sub> Adrenoceptors

et al. 1999

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This study was designed to examine the importance of interaction in the bindings of nonselective β-blockers to β₁-adrenoceptors (β₁-ARs) as compared with β₂-ARs, using molecular modeling. The β-blockers used in this study were bopindolol [4-(benzoyloxy-3-t- butylaminopropyl)-2-methylindol hydrogen malomate], its two metabolites [18-502 – hydrolyzed bopindolol or 4-(3-t-butylamino-2-hydroxypropoxy)-2-methyl indole – and 20-785 – 4-(3-t-butylaminopropoxy)-2-carboxyl indole], and propranolol. Molecular modeling was performed on an Indigo2 workstation (Silicon Graphic) using Discover/Insight II (Molecular Simulations) software. Through molecular modeling, possible binding sites for these drugs were suggested to lie between helices 3, 4, 5, and 6 of the β₁-AR. The amine, benzoic acid, indole methyl, t-butyl, phenyl, and indole functional groups of bopindolol possibly interact with Asp138 (transmembrane – TM – 3), Ser190 (TM 4), Ala343 (TM 6), Val137 (TM 3), Pro339 (TM6), Cys336 (TM 4), Leu237 (TM 5), and Pro236 (TM 5) of β₁-AR, respectively, by either hydrogen bonding or hydrophobic interactions. In addition, 18-502, 20-785, and propranolol also interacted with sites at the same positions as those of β₂-ARs. Thus, the results of the present study suggested that although Ala343 and Val137 of β₁-AR among these amino acids were different from those of β₂-AR, the interactions at the same sites between ligands and amino acids of β₁-AR as those of β₂-ARs may occur because these drugs are nonselective.

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Albinus¹,

Amschler²,

Angerer³

et al. 1999

Hagers Handbuch Der Pharmazeutischen Praxis

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Beta-blocking Potency and Selectivity of Bopindolol an Its Two Metabolites for .BETA.1- and .BETA.2-Adrenergic Receptors as Assessed by Radioligand Binding Assay.

Cited by 10 publications

References 17 publications

Bopindolol: A Slowly Dissociating Antagonist from the β-Adrenoceptors in Guinea Pig Atria

Bopindolol: A Slowly Dissociating Antagonist from the β-Adrenoceptors in Guinea Pig Atria

Identification of Binding Sites of Bopindolol and Its Two Metabolites with β<sub>1</sub>-Adrenoceptors by Molecular Modeling: Comparison with β<sub>2</sub> Adrenoceptors

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