Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 11229-11240 |
| Number of pages | 12 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 65 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - 25 Aug 2022 |
Keywords
- Animals
- Circadian Rhythm
- Ligands
- Melatonin/metabolism
- Rats
- Receptor, Melatonin, MT1/chemistry
- Receptor, Melatonin, MT2/metabolism
- Receptors, Melatonin