Studies on relationships between chemical structure and β-blocking potency of bopindolol and its two metabolites

Nagatomo, Takafumi; Ishiguro, Masaji; Ohnuki, Toshio; Hattori, Kaoru; Hosohata, Yoshiaki; Takatsu, Noriyuki; Katayama, Hajime; Watanabe, Kenichi

doi:10.1016/s0024-3205(98)00113-1

Cited by 10 publications

(15 citation statements)

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“…These authors also indicated that derivatization of TM6 and TM7 by these photolabelled compounds suggests the folded conformation of these compounds in the ligand binding pocket. On the other hand, our laboratory deduced 3D structures of human >-ARs and profiles of >-AR antagonists binding by computer simulation based on the electron density map of rhodopsin (34,35). This modeling analysis supported the results of molecular biological-/pharmacological-experiments and further gave us some novel interesting suggestions.…”

Section: Analysis Of Binding Sites In > > > >-Ar Subtypes By Moleculamentioning

confidence: 52%

β -Adrenoceptors: Three-Dimensional Structures and Binding Sites for Ligands

Nagatomo

Ohnuki

Ishiguro

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-Recent progress in analyzing the structures and functions of G-protein coupled receptors (GPCRs) including > -adrenoceptors (>-ARs) has been made by pharmacological, physiological and molecular biological techniques. The three-dimensional (3D) structures, interaction sites with ligands and conformational changes of these receptor subtypes due to ligand binding are now better understood by the simulation of these receptors using computer-aided molecular modeling. Based on these techniques, numbers and conformations of amino acid sequences of each subtype (> 1-, >2-and >3-ARs) were defined and also interaction sites or modes of interaction between ligands and >-ARs could be analyzed three-dimensionally. In addition, simulation of 3D structures of > -ARs by molecular modeling could clearly determine the limited size, space or pocket for fitting with ligands. These studies will give some clues for the clarification of other GPCRs. Thus, this review summarizes current findings on chemical structures of ligands, amino acid sequences, 3D structures and important amino acids of >-AR subtypes for interacting with ligands obtained from mutagenesis, chimeric studies and molecular modeling techniques.

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Section: Analysis Of Binding Sites In > > > >-Ar Subtypes By Moleculamentioning

confidence: 52%

β -Adrenoceptors: Three-Dimensional Structures and Binding Sites for Ligands

Nagatomo

Ohnuki

Ishiguro

et al. 2001

Japanese Journal of Pharmacology

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“…indole, amine, t-butyl, and benzoyl groups, possibly interact with Trp134 (TM 3), Val137 (TM 3), Asp138 (TM 3), Ser190 (TM 4), Phe233 (TM 5), Pro236 (TM 5), Leu237 (TM 5), Pro339 (TM 6), Cys336 (TM 6), Phe340 (TM 6), and Ala343 (TM 6) in the 3, 4, 5, and 6 helices of ß 1 -ARs. It is, however, of interest that these amino acids of ß 1 -AR possibly bind functional groups of bopindolol at the same positions as those of ß 2 -AR reported by Nagatomo et al [1], although Val137 (TM 3) and Ala343 (TM 6) of the ß 1 -AR are different from Ile112 and Val292 of ß 2 -ARs, respectively. In particular, Val292 of ß 2 -ARs interacts with a methyl residue of the indole ring of bopindolol and 18-502, and this region formed a pocket for interaction with this methyl by hydrophobic binding.…”

Section: Discussionmentioning

confidence: 77%

“…Previously, we also hypothesized on the interacting sites between the functional groups of these drugs and amino acids of ß 2 -AR and the regions docking to the sites between helices 3, 4, 5, and 6 with the side chains of the ß 2 -ARs according to molecular modeling [1]. Thus, it is very important to evaluate and compare binding sites of interactions between these drugs and amino acids of ß 1 -and ß 2 -AR subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…Analyses of the interaction between ligands and amino acid sequences of ß 1 -ARs were performed according to the report of Nagatomo et al [1]. Briefly, the amino acid sequences of ß 1 -ARs reported by Frielle et al [9] were used for the construction of seven transmembrane (TM) helices using Discover/Insight II software.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous study [1] clearly identified the sites of interaction of the nonselective ß-adrenoceptor (AR) antagonist bopindolol (benzoyloxy-3-t-butylaminopropyl-2-methylindol hydrogen malomate) and amino acids of human ß 2 -AR using molecular modeling. Human ß 1 -AR is a member of the G protein coupled superfamily of receptors [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

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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.