Binding Kinetics of ZM241385 Derivatives at the Human Adenosine A2A Receptor. Issue 4 (3rd March 2014)

• Record Type: Journal Article
• Authors: Guo, Dong; Xia, Lizi; van Veldhoven, Jacobus P. D.; Hazeu, Marc; Mocking, Tamara; Brussee, Johannes; IJzerman, Adriaan P.; Heitman, Laura H.
• Is Part Of: ChemMedChem. Volume 9:Issue 4(2014:Apr.)
• Page Start: 752
• Page End: 761
• Publication Date: 2014-03-03
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300474
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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_2AR). The ensemble of 24 A_2AR compounds, all triazolotriazine derivatives resembling the prototypic antagonist ZM241385 (4‐(2‐((7‐amino‐2‐(furan‐2‐yl)‐[1, 2, 4]triazolo[1, 5‐<italic>a</italic>][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_2AR, 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.</p> </abstract>