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Binding Kinetics of ZM241385 Derivatives at the Human Adenosine A 2A Receptor
Author(s) -
Guo Dong,
Xia Lizi,
van Veldhoven Jacobus P. D.,
Hazeu Marc,
Mocking Tamara,
Brussee Johannes,
IJzerman Adriaan P.,
Heitman Laura H.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300474
Subject(s) - kinetics , stereochemistry , chemistry , receptor , adenosine receptor , ligand (biochemistry) , receptor–ligand kinetics , potency , antagonist , g protein coupled receptor , biophysics , biochemistry , in vitro , biology , physics , quantum mechanics , agonist
Classical drug design and development rely mostly on affinity‐ or potency‐driven structure–activity relationships (SAR). Thus far, a given compound’s binding kinetics have been largely ignored, the importance of which is now being increasingly recognized. In the present study, we performed an extensive structure–kinetics relationship (SKR) study in addition to a traditional SAR analysis at the adenosine A 2A receptor (A 2A R). The ensemble of 24 A 2A R compounds, all triazolotriazine derivatives resembling the prototypic antagonist ZM241385 (4‐(2‐((7‐amino‐2‐(furan‐2‐yl)‐[1,2,4]triazolo[1,5‐ a ][1,3,5]triazin‐5‐yl)amino)ethyl)phenol), displayed only minor differences in affinity, although they varied substantially in their dissociation rates from the receptor. We believe that such a combination of SKR and SAR analyses, as we have done with the A 2A R, will have general importance for the superfamily of G protein‐coupled receptors, as it can serve as a new strategy to tailor the interaction between ligand and receptor.