GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A_2A Adenosine Receptor.

ABSTRACT: Modulators of the G protein-coupled A_2A adenosine receptor (A_2AAR) have been considered promising agents to treat Parkinson's disease, inflammation, cancer, and central nervous system disorders. Herein, we demonstrate that a thiophene modification at the C8 position in the common adenine scaffold converted an A_2AAR agonist into an antagonist. We synthesized and characterized a novel A_2AAR antagonist, 2 (LJ-4517), with K_i = 18.3 nM. X-ray crystallographic structures of 2 in complex with two thermostabilized A_2AAR constructs were solved at 2.05 and 2.80 Å resolutions. In contrast to A_2AAR agonists, which simultaneously interact with both Ser277^7.42 and His278^7.43, 2

SUBMITTER: Shiriaeva A 

PROVIDER: S-EPMC9469204 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature