posted on 2024-01-26, 14:35authored byAnaëlle Dumazer, Xavier Gómez-Santacana, Fanny Malhaire, Chris Jopling, Damien Maurel, Guillaume Lebon, Amadeu Llebaria, Cyril Goudet
In
recent years, there has been growing interest in the potential
therapeutic use of inhibitors of adenosine A2A receptors
(A2AR) for the treatment of neurodegenerative diseases
and cancer. Nevertheless, the widespread expression of A2AR throughout the body emphasizes the importance of temporally and
spatially selective ligands. Photopharmacology is an emerging strategy
that utilizes photosensitive ligands to attain high spatiotemporal
precision and regulate the function of biomolecules using light. In
this study, we combined photochemistry and cellular and in vivo photopharmacology
to investigate the light sensitivity of the FDA-approved antagonist
istradefylline and its potential use as an A2AR photopharmacological
tool. Our findings reveal that istradefylline exhibits rapid trans-to-cis
isomerization under near-UV light, and prolonged exposure results
in the formation of photocycloaddition products. We demonstrate that
exposure to UV light triggers a time-dependent decrease in the antagonistic
activity of istradefylline in A2AR-expressing cells and
enables real-time optical control of A2AR signaling in
living cells and zebrafish. Together, these data demonstrate that
istradefylline is a photoinactivatable A2AR antagonist
and that this property can be utilized to perform photopharmacological
experiments in living cells and animals.