Binding Kinetics of ZM241385 Derivatives at the Human Adenosine A2A Receptor

• Published in: ChemMedChem Vol. 9; no. 4; pp. 752 - 761
• Main Authors: Guo, Dong, Xia, Lizi, van Veldhoven, Jacobus P. D., Hazeu, Marc, Mocking, Tamara, Brussee, Johannes, IJzerman, Adriaan P., Heitman, Laura H.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.04.2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Adenosine A2 Receptor Antagonists - chemical synthesis; Adenosine A2 Receptor Antagonists - chemistry; Adenosine A2 Receptor Antagonists - pharmacology; antagonism; binding kinetics; Binding Sites; Dose-Response Relationship, Drug; G protein-coupled receptors; Humans; Kinetics; Molecular Structure; Receptor, Adenosine A2A - metabolism; Structure-Activity Relationship; structure-activity relationships; structure-kinetics relationships; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; G protein-coupled receptors; antagonism; structure-activity relationships; structure-kinetics relationships; binding kinetics
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201300474

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 A2A receptor (A2AR). The ensemble of 24 A2AR 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 A2AR, 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. Above and beyond: Insight into the binding kinetics of ZM241385 derivatives at the human adenosine A2A receptor has provided additional information beyond a traditional structure–activity relationship (SAR) analysis. The strategy, combining a structure–kinetics relationship investigation and SAR, can serve as an important tool for more directed medicinal chemistry efforts in the future.