학술논문

Structure–Affinity Relationships and Structure–Kinetics Relationships of Pyrido[2,1-f]purine-2,4-dione Derivatives as Human Adenosine A3Receptor Antagonists
Document Type
Article
Source
Journal of Medicinal Chemistry; 20240101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
We expanded on a series of pyrido[2,1-f]purine-2,4-dione derivatives as human adenosine A3receptor (hA3R) antagonists to determine their kinetic profiles and affinities. Many compounds showed high affinities and a diverse range of kinetic profiles. We found hA3R antagonists with very short residence time (RT) at the receptor (2.2 min for 5) and much longer RTs (e.g., 376 min for 27or 391 min for 31). Two representative antagonists (5and 27) were tested in [35S]GTPγS binding assays, and their RTs appeared correlated to their (in)surmountable antagonism. From a kon–koff–KDkinetic map, we divided the antagonists into three subgroups, providing a possible direction for the further development of hA3R antagonists. Additionally, we performed a computational modeling study that sheds light on the crucial receptor interactions, dictating the compounds’ binding kinetics. Knowledge of target binding kinetics appears useful for developing and triaging new hA3R antagonists in the early phase of drug discovery.