Abstract

The β(2) adrenergic receptor (β(2)-AR) is a model system for studying the ligand recognition process in G protein-coupled receptors. Fenoterol (FEN) is a β(2)-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 G(s) protein signaling while the (S,R')-isomer activated both G(i) and G(s) 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 β(2)-AR activation. Differences in thermodynamic parameters and nonuniform 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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Authors

Jozwiak K, Plazinska A, Toll L, Jimenez L, Woo AY, Xiao RP, Wainer IW

Institution

Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, Lublin, Poland. krzysztof.jozwiak@umlub.pl

Source

Chirality 23 Suppl 1: 2011 pg E1-6

MeSH

Adrenergic beta-2 Receptor Agonists
Animals
Cell Line, Tumor
Entropy
Fenoterol
GTP-Binding Proteins
Hot Temperature
Humans
Kinetics
Ligands
Models, Chemical
Rats
Receptors, Adrenergic, beta-2
Stereoisomerism
Structure-Activity Relationship
Temperature
Thermodynamics

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

21618615