1608157-07-8Relevant articles and documents
Binding kinetics of ZM241385 derivatives at the human adenosine A 2A receptor
Guo, Dong,Xia, Lizi,Van Veldhoven, Jacobus P. D.,Hazeu, Marc,Mocking, Tamara,Brussee, Johannes,Ijzerman, Adriaan P.,Heitman, Laura H.
, p. 752 - 761 (2014/05/06)
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 (A 2AR). 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 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. 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.
