Design and Validation of the First Family of Photo-Activatable Ligands for Melatonin Receptors

Melatonin is a neurohormone released in a circadian manner
with
peak levels at night. Melatonin mediates its effects mainly through
G protein-coupled MT1 and MT2 receptors. Drugs
acting on melatonin receptors are indicated for circadian rhythm-
and sleep-related disorders. Tools to study the activation of these
receptors with high temporal resolution are lacking. Here, we synthesized
a family of light-activatable caged compounds by attaching o-nitrobenzyl (o-NB) or coumarin photocleavable
groups to melatonin indolic nitrogen. All caged compounds showed the
expected decrease in binding affinity for MT1 and MT2. The o-NB derivative MCS-0382 showed the
best uncaging and biological properties, with 250-fold increase in
affinity and potency upon illumination. Generation of melatonin from
MCS-0382 was further demonstrated by its ability to modulate the excitation
of SCN neurons in rat brain slices. MCS-0382 is available to study
melatonin effects in a temporally controlled manner in cellular and
physiological settings.