Design, synthesis and biological evaluation of fluorescent ligands for MT1 and/or MT2 melatonin receptors

International audienceMelatonin (N-acetyl-5-methoxytryptamine) is a neurohormone synthesized by the pineal glandduring the dark period in all animal species and immediately released. The rhythm of melatoninsynthesis is directly controlled by photoperiod. Melatonin secretion both in blood and incerebrospinal fluid transduces the photoperiodic message to all central or peripheral structuresexpressing melatoninergic receptors or binding sites, allowing synchronization of several cellularand physiological events to a given day-length. Melatonin rhythm synchronizes a wide range ofphysiological functions including among others circadian rhythms, seasonal reproduction,immunity etc. Anarchic melatonin secretion also accounts for disorders of sleep/wake rhythmsassociated or not with depression.Fluorescent melatoninergic ligands (Viault, G., et al. RSC Adv. 2016, 6, 62508–62521) weredesigned by associating the 4-azamelatonin ligands with different fluorophores. The ligands showgood affinities for MT1 and/or MT2 receptors and substitution of the fluorophore at positions 2 or 5of the azamelatonin core had a direct impact on the MT receptors selectivity while grafting thefluorophores on position N-1 produced fluorescent ligands with good affinities for both MT1/MT2receptors. The optimal position N-1, C-2 or C-5 on the 4-azamelatonin ligand appeared stronglydependent upon the nature of the fluorophore itself