Development of Covalent Ligands for G Protein-Coupled Receptors: A Case for the Human Adenosine A Receptor.

The development of covalent ligands for G protein-coupled receptors (GPCRs) is not a trivial process. Here, we report a streamlined workflow thereto from synthesis to validation, exemplified by the discovery of a covalent antagonist for the human adenosine A receptor (hAAR). Based on the 1 H,3 H-pyrido[2,1- f]purine-2,4-dione scaffold, a series of ligands bearing a fluorosulfonyl warhead and a varying linker was synthesized.

Structure-Affinity Relationships and Structure-Kinetics Relationships of Pyrido[2,1-f]purine-2,4-dione Derivatives as Human Adenosine A Receptor Antagonists.

We expanded on a series of pyrido[2,1-f]purine-2,4-dione derivatives as human adenosine A receptor (hAR) antagonists to determine their kinetic profiles and affinities. Many compounds showed high affinities and a diverse range of kinetic profiles. We found hAR antagonists with very short residence time (RT) at the receptor (2.