β<sub>1</sub>-Selective Agonist (−)-1-(3,4-Dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(−)-RO363] Differentially Interacts with Key Amino Acids Responsible for β<sub>1</sub>-Selective Binding in Resting and Active States

Sugimoto, Yohei; Fujisawa, Reiko; Tanimura, Ryuji; Lattion, Anne Laure; Cotecchia, Susanna; Tsujimoto, Gozoh; Nagao, Taku; Kurose, Hitoshi

doi:10.1124/jpet.301.1.51

Cited by 16 publications

(16 citation statements)

References 38 publications

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“…The implication of residues Leu2.64 and Ser7.36 in ligand binding, as proposed by our models, has been corroborated by mutagenesis experiments 25. 30, 31 It should be mentioned that the D 3 receptor binding site is very similar to that of the D 2 receptor, as they are nearly identical in sequence at this region. However, the Leu1.39 residue present in the D 2 receptor site is replaced in the D 3 receptor site by Tyr1.39, which interacts with Glu2.65 (Figure 5 b), and thus does not exhibit the SEW interaction network described above (Figure 5 a).…”

Section: Resultssupporting

confidence: 82%

Synthesis, 3D‐QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D₂ and D₃ Receptors

López¹,

Selent²,

Ortega³

et al. 2010

ChemMedChem

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A series of 37 benzolactam derivatives were synthesized, and their respective affinities for the dopamine D(2) and D(3) receptors evaluated. The relationships between structures and binding affinities were investigated using both ligand-based (3D-QSAR) and receptor-based methods. The results revealed the importance of diverse structural features in explaining the differences in the observed affinities, such as the location of the benzolactam carbonyl oxygen, or the overall length of the compounds. The optimal values for such ligand properties are slightly different for the D(2) and D(3) receptors, even though the binding sites present a very high degree of homology. We explain these differences by the presence of a hydrogen bond network in the D(2) receptor which is absent in the D(3) receptor and limits the dimensions of the binding pocket, causing residues in helix 7 to become less accessible. The implications of these results for the design of more potent and selective benzolactam derivatives are presented and discussed.

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Section: Resultssupporting

confidence: 82%

Synthesis, 3D‐QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D₂ and D₃ Receptors

López¹,

Selent²,

Ortega³

et al. 2010

ChemMedChem

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“…However, our simulations produce similar PMF profiles for C1 and C2 in both receptors and, thus, both routes may serve indistinguishably for the entry and exit of inverse agonists. Importantly, all the TM residues identified in our study have been experimentally found to be involved in ligand interactions for βARs or/and other GPCRs: 2.64 [35], [36], 2.65 [37], [38], 3.28 [39], [40], 5.36 [41], 6.55 [42], 6.58 [43], [44], 7.35 [38], [45], 7.36 [46], 7.39 [47] and 7.40 [48]. Also, as the two channels are connected through the orthosteric binding site, we cannot rule out the possibility that ligands could use one route for entry and the other for exit, in the same manner as proposed for the uptake and release of retinal in rhodopsin [23].…”

Section: Discussionmentioning

confidence: 79%

Molecular Basis of Ligand Dissociation in β-Adrenergic Receptors

et al. 2011

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The important and diverse biological functions of β-adrenergic receptors (βARs) have promoted the search for compounds to stimulate or inhibit their activity. In this regard, unraveling the molecular basis of ligand binding/unbinding events is essential to understand the pharmacological properties of these G protein-coupled receptors. In this study, we use the steered molecular dynamics simulation method to describe, in atomic detail, the unbinding process of two inverse agonists, which have been recently co-crystallized with β1 and β2ARs subtypes, along four different channels. Our results indicate that this type of compounds likely accesses the orthosteric binding site of βARs from the extracellular water environment. Importantly, reconstruction of forces and energies from the simulations of the dissociation process suggests, for the first time, the presence of secondary binding sites located in the extracellular loops 2 and 3 and transmembrane helix 7, where ligands are transiently retained by electrostatic and Van der Waals interactions. Comparison of the residues that form these new transient allosteric binding sites in both βARs subtypes reveals the importance of non-conserved electrostatic interactions as well as conserved aromatic contacts in the early steps of the binding process.

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“…This high conservation in the ligand-binding pocket is also observed in other subfamilies of GPCRs (such as dopamine, serotonin and histamine), and probably explains some of the difficulty in obtaining potent subtype-selective compounds in pharmaceutical discovery programs 32 . Nevertheless, subtype-specific binding affinities are observed for β 1 AR and β 2 AR 33,34 . These differences cannot be based primarily on the amino acids forming the binding pocket, but involve more subtle influences on the arrangement of these amino acids as a result of subtype-specific conformational preferences in more distant residues.…”

Section: The Inactive States Of Four Gpcrsmentioning

confidence: 94%

The structure and function of G-protein-coupled receptors

Rosenbaum

Rasmussen

Kobilka

2009

Nature

2,103

1,700

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G-protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants, and so have great potential as therapeutic targets for a broad spectrum of diseases. They are also fascinating molecules from the perspective of membrane-protein structure and biology. Great progress has been made over the past three decades in understanding diverse GPCRs, from pharmacology to functional characterization in vivo. Recent high-resolution structural studies have provided insights into the molecular mechanisms of GPCR activation and constitutive activity.

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β₁-Selective Agonist (−)-1-(3,4-Dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(−)-RO363] Differentially Interacts with Key Amino Acids Responsible for β₁-Selective Binding in Resting and Active States

Cited by 16 publications

References 38 publications

Synthesis, 3D‐QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D₂ and D₃ Receptors

Synthesis, 3D‐QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D₂ and D₃ Receptors

Molecular Basis of Ligand Dissociation in β-Adrenergic Receptors

The structure and function of G-protein-coupled receptors

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β1-Selective Agonist (−)-1-(3,4-Dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(−)-RO363] Differentially Interacts with Key Amino Acids Responsible for β1-Selective Binding in Resting and Active States

Cited by 16 publications

References 38 publications

Synthesis, 3D‐QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D2 and D3 Receptors

Synthesis, 3D‐QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D2 and D3 Receptors

Molecular Basis of Ligand Dissociation in β-Adrenergic Receptors

The structure and function of G-protein-coupled receptors

Contact Info

Product

Resources

About

β₁-Selective Agonist (−)-1-(3,4-Dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(−)-RO363] Differentially Interacts with Key Amino Acids Responsible for β₁-Selective Binding in Resting and Active States

Synthesis, 3D‐QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D₂ and D₃ Receptors

Synthesis, 3D‐QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D₂ and D₃ Receptors