Crystal Structure and Subsequent Ligand Design of a Nonriboside Partial Agonist Bound to the Adenosine A 2A Receptor

In this study, we determined the crystal structure of an engineered human adenosine A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dic...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-04, Vol.64 (7), p.3827-3842
Main Authors: Amelia, Tasia, van Veldhoven, Jacobus P D, Falsini, Matteo, Liu, Rongfang, Heitman, Laura H, van Westen, Gerard J P, Segala, Elena, Verdon, Grégory, Cheng, Robert K Y, Cooke, Robert M, van der Es, Daan, IJzerman, Adriaan P
Format: Article
Language:English
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Summary:In this study, we determined the crystal structure of an engineered human adenosine A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dicyanopyridines, and amino acids in the ligand binding pocket inspired us to develop a small library of derivatives and assess their affinity in radioligand binding studies and potency and intrinsic activity in a functional, label-free, intact cell assay. It appeared that some of the derivatives retained the partial agonist profile, whereas other ligands turned into inverse agonists. We rationalized this remarkable behavior with additional computational docking studies.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01856