title: Binding kinetics of ZM241385 derivatives at the human adenosine A2A receptor.
abstract: 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 (A2A R). The ensemble of 24 A2A 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 A2A 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.
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.forename: Lizi
authors.initials: L
authors.lastname: Xia
authors.forename: Jacobus P D
authors.initials: JP
authors.lastname: van Veldhoven
authors.forename: Marc
authors.initials: M
authors.lastname: Hazeu
authors.forename: Tamara
authors.initials: T
authors.lastname: Mocking
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385
keywords: G protein-coupled receptors; antagonism; binding kinetics; structure-activity relationships; structure-kinetics relationships