The effect of stereochemistry on the thermodynamic characteristics of the binding of fenoterol stereoisomers to the beta(2)-adrenoceptor.
The binding thermodynamics of the stereoisomers of fenoterol, (R,R')-, (S,S')-, (R,S')-, and (S,R')-fenoterol, to the beta(2)-adrenergic receptor (beta(2)-AR) have been determined. The experiments utilized membranes obtained from HEK cells stably transfected with cDNA encoding human beta(2)-AR. Competitive displacement studies using [(3)H]CGP-12177 as the marker ligand were conducted at 4, 15, 25, 30 and 37 degrees C, the binding affinities calculated and the standard enthalpic (DeltaH degrees ) and standard entropic (DeltaS degrees ) contribution to the standard free energy change (DeltaG degrees ) associated with the binding process determined through the construction of van't Hoff plots. The results indicate that the binding of (S,S')- and (S,R')-fenoterol were predominately enthalpy-driven processes while the binding of (R,R')- and (R,S')-fenoterol were entropy-driven. All of the fenoterol stereoisomers are full agonists of the beta(2)-AR, and, therefore, the results of this study are inconsistent with the previously described "thermodynamic agonist-antagonist discrimination", in which the binding of an agonist to the beta-AR is entropy-driven and the binding of an antagonist is enthalpy-driven. In addition, the data demonstrate that the chirality of the carbon atom containing the beta-hydroxyl group of the fenoterol molecule (the beta-OH carbon) is a key factor in the determination of whether the binding process will be enthalpy-driven or entropy-driven. When the configuration at the beta-OH carbon is S the binding process is enthalpy-driven while the R configuration produces an entropy-driven process.
Department of Chemistry, Medical University of Lublin, Poland. krzysztof.jozwiak@umlub.pl
Krzysztof
K
Jozwiak
Lawrence
L
Toll
Lucita
L
Jimenez
Anthony Yiu-Ho
AY
Woo
Rui-Ping
RP
Xiao
Irving W
IW
Wainer
D000318:Adrenergic beta-Agonists / Q000737:chemistry* / Q000493:pharmacokinetics; D001667:Binding, Competitive; D002460:Cell Line; D005280:Fenoterol / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D011485:Protein Binding; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013237:Stereoisomerism; D013816:Thermodynamics
D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D005280:Fenoterol