The effect of stereochemistry on the thermodynamic characteristics of the binding of fenoterol stereoisomers to the β2-adrenoceptor

Jóźwiak, Krzysztof; Toll, Lawrence; Jimenez, Lucita; Woo, Anthony Yiu-Ho; Xiao, Rui‐Ping; Wainer, Irving W.

doi:10.1016/j.bcp.2010.01.035

Cited by 26 publications

(40 citation statements)

References 14 publications

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“…Furthermore, this prediction of the thermodynamic data suggests, that the differences in enthalpic and entropic terms may be related with the preferred binding mode of the chiral phenoprodifen derivatives [13]. Similar studies were performed for four fenoterol stereoisomers at the adrenergic β 2 receptor [8]. Since the studied fenoterol stereoisomers include two enantomeric pairs: (S,S')-(R,R') and (S,R')-(R,S'), the resulting data of the corresponding enantiomers can be directly related the β 2 R-fenoterol-complex and desolvation terms have no influence.…”

Section: Antagonists (Partial) Agonistssupporting

confidence: 55%

“…At the histamine H 1 receptor [13], and the adrenergic β 2 receptor (hβ 2 R), the enthalpy and entropy of ligand binding was studied for chiral compounds, including both enantiomers [8,9]. As mentioned above, the enthalpy and entropy of desolvation of the ligand is suggested to have an influence onto enthalpy and entropy of ligand binding to a target.…”

Section: Chiral Compounds and Thermodynamics Of Ligand Bindingmentioning

confidence: 99%

“…Furthermore, since the fenoterol derivatives act as full agonists at the β 2 R, different conformations of the β 2 R have to be taken into account. The authors relate the chirality of the carbon atom containing the β-OH-moiety as a key factor, with regard to enthalpy-or entropydriven binding process of a fenoterol stereoisomer [8]. R-configuration leads to an entropy-driven binding process, whereas for S-configuration an enthalpy-driven binding process was observed.…”

Section: Antagonists (Partial) Agonistsmentioning

confidence: 99%

“…Weiland et al (1979) were the first, who observed a thermodynamic discrimination of antagonists and agonists at the β-adrenergic receptor [6]. Subsequently, a large number of studies at different GPCRs were performed in order to determine thermodynamics of ligand binding: For example, addressing the β 2 adrenergic receptor [6][7][8][9], the serotonin 5-HT 1A -receptor [10], the dopamine D 2 receptor [11,12], the histamine H 1 receptor [13] and the histamine H 3 receptor [14]. These receptors belong to the aminergic GPCRs of the GPCR family A [3].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Binding of Ligands to GPCRs ? How Valid is a Thermodynamic Discrimination of Antagonists and Agonists?

Straßer¹,

Wittmann²

2012

J Phys Chem Biophys

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Section: Antagonists (Partial) Agonistssupporting

confidence: 55%

Section: Chiral Compounds and Thermodynamics Of Ligand Bindingmentioning

confidence: 99%

Section: Antagonists (Partial) Agonistsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Binding of Ligands to GPCRs ? How Valid is a Thermodynamic Discrimination of Antagonists and Agonists?

Straßer¹,

Wittmann²

2012

J Phys Chem Biophys

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“…1) (Jozwiak et al, 2007(Jozwiak et al, , 2010aToll et al, 2011). During the course of these studies, we determined the binding thermodynamics of the four stereoisomers of Fen, (R,RЈ)-, (R,SЈ)-, (S,RЈ)-, and (S,SЈ)-Fen to the ␤ 2 -AR (Jozwiak et al, 2010a).…”

Section: Introductionmentioning

confidence: 99%

Thermodynamics and Docking of Agonists to the β2-Adrenoceptor Determined Using [3H](R,R′)-4-Methoxyfenoterol as the Marker Ligand

Toll¹,

Pająk²,

Płazińska³

et al. 2012

Molecular Pharmacology

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G protein-coupled receptors (GPCRs) are integral membrane proteins that change conformation after ligand binding so that they can transduce signals from an extracellular ligand to a variety of intracellular components. The detailed interaction of a molecule with a G protein-coupled receptor is a complicated process that is influenced by the receptor conformation, thermodynamics, and ligand conformation and stereoisomeric configuration. To better understand the molecular interactions of fenoterol analogs with the ␤ 2 -adrenergic receptor, we developed a new agonist radioligand for binding assays. [3 H](R,RЈ)-methoxyfenoterol was used to probe the binding affinity for a series of fenoterol stereoisomers and derivatives. The results suggest that the radioligand binds with high affinity to an agonist conformation of the receptor, which represents approximately 25% of the total ␤ 2 -adrenoceptor (AR) population as determined with the antagonist [ 3 H]CGP-12177. The ␤ 2 -AR agonists tested in this study have considerably higher affinity for the agonist conformation of the receptor, and K i values determined for fenoterol analogs model much better the cAMP activity of the ␤ 2 -AR elicited by these ligands. The thermodynamics of binding are also different when interacting with an agonist conformation, being purely entropy-driven for each fenoterol isomer, rather than a mixture of entropy and enthalpy when the fenoterol isomers binding was determined using [ 3 H]CGP-12177. Finally, computational modeling identified the molecular interactions involved in agonist binding and allow for the prediction of additional novel ␤ 2 -AR agonists. The study underlines the possibility of using defined radioligand structure to probe a specific conformation of such shape-shifting system as the ␤ 2 -adrenoceptor.

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Effect of fenoterol stereochemistry on the β2 adrenergic receptor system: Ligand‐directed chiral recognition

et al. 2011

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The β2 adrenergic receptor (β2-AR) is a model system for studying the ligand recognition process in G-protein coupled receptors. Fenoterol (FEN) is a β2-AR selective agonist that has two centers of chirality and exists as four stereoisomers. Radioligand binding studies determined that stereochemistry greatly influences the binding affinity. Subsequent Van’t Hoff analysis shows very different thermodynamics of binding depending on the stereoconfiguration of the molecule. The binding of (S,x’)-isomers is almost entirely enthalpy controlled whereas binding of (R,x’)-isomers is purely entropy driven. Stereochemistry of FEN molecule also affects the coupling of the receptor to different G proteins. In a rat cardiomyocyte contractility model, (R,R’)-FEN was shown to selectively activate Gs protein signaling while the (S,R’)- isomer activated both Gi and Gs protein. The overall data demonstrate that the chirality at the two chiral centers of the FEN molecule influences the magnitude of binding affinity, thermodynamics of local interactions within the binding site and the global mechanism of β2-AR activation. Differences in thermodynamic parameters and non-uniform G-protein coupling suggest a mechanism of chiral recognition in which observed enantioselectivities arise from the interaction of the (R,x’)-FEN stereoisomers with a different receptor conformation than the one with which the (S,x’)-isomer interacts.

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The effect of stereochemistry on the thermodynamic characteristics of the binding of fenoterol stereoisomers to the β2-adrenoceptor

Cited by 26 publications

References 14 publications

Binding of Ligands to GPCRs ? How Valid is a Thermodynamic Discrimination of Antagonists and Agonists?

Binding of Ligands to GPCRs ? How Valid is a Thermodynamic Discrimination of Antagonists and Agonists?

Thermodynamics and Docking of Agonists to the β2-Adrenoceptor Determined Using [3H](R,R′)-4-Methoxyfenoterol as the Marker Ligand

Effect of fenoterol stereochemistry on the β2 adrenergic receptor system: Ligand‐directed chiral recognition

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