Skip to main content

Targeted covalent modification of the A2A adenosine receptor by acyl transfer

Wednesday, November 06, 2013 — Poster Session I

4:00 p.m. – 6:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • S.M. Moss
  • P.S. Jayasekara
  • S. Paoletta
  • Z.G. Gao
  • K.A. Jacobson


Adenosine receptors (ARs) are members of the G protein-coupled receptor (GPCR) superfamily, and have shown much promise as therapeutic drug targets. The A2A-AR subtype is of particular interest being the only AR subtype structurally elucidated with X-ray crystallography, including agonist- and antagonist-bound structures. To further explore and chemically engineer the A2A-AR binding cavity, an active ester for transfer of a terminal acetyl group was attached to a 2-nitrophenol moiety incorporated on the C2 chain of the selective A2A-AR agonist ligand CGS21680. This labeling reagent is intended to target specific lysines (K150 and K153) in the second extracellular loop (EL), as predicted with in silico docking of the compound in the receptor. When incubated with membranes of HEK293 cells overexpressing the A2AAR followed by extensive washing to remove excess ligand, the binding of agonist [3H]CGS21680 and antagonist [3H]ZM521385 radioligands were reduced to 19% and 12%, respectively. Then, the active acyl group for transfer was elongated into an alkyl azide for envisioned Cu-free click reactions with the receptor. This compound also irreversibly reduced agonist and antagonist radioligand binding. These promising results indicate a stable, covalent modification of the receptor, which has future implications in neurological imaging and drug design.

back to top