Melatonin, a neurohormone produced in the pineal gland, governs sleep-wake cycles and body temperature rhythms. Its secretion follows a circadian pattern, synchronized by light exposure: increasing in the evening, peaking around 3:00 a.m., and declining in the early morning. The hypnotic impact of melatonin is believed to stem from MT receptor activation: MT1 receptor regulates REM sleep, while MT2 receptor modulates NREM sleep. Therefore, Ramelteon (TAK-375), an analogue of melatonin, can be used for sleep disturbances research. Ramelteon is an orally active and selective agonist for MT1/MT2 receptors, and promotes sleep through Gi coupling. Besides, activation of these MT receptors induces different sleep stages, influencing either REM or NREM sleep.

Ramelteon is an orally active and selective MT1/MT2 receptor agonist for sleep disturbances research.

In vivo, Ramelteon, administered orally at doses of 0.1 and 1 mg/kg, hastens the reentrainment of running wheel activity rhythms to a new light-dark cycle. In rats, oral doses ranging from 3 to 30 mg/kg do not impact learning or memory based on water maze and delayed match to position tasks, suggesting that MT1/MT2 receptor agonists lack abuse potential. At lower doses (0.0001-0.1 mg/kg) taken orally over 8 hours, Ramelteon notably reduces wakefulness at 0.001, 0.01, and 0.1 mg/kg, enhances slow-wave sleep between 0.001 and 0.1 mg/kg, and augments rapid eye movement sleep specifically at 0.1 mg/kg.

In summary, Ramelteon is an analogue of melatonin, and can be used for sleep disturbance research, such as insomnia. Ramelteon is also effective in reducing the latency to sleep and night awakenings while increasing total sleep time.

References:

[1] Maurer JJ, et al. Neurobiol Sleep Circadian Rhythms. 2023 Apr 26;14:100095.
[2] Hirai K, et al. J Biol Rhythms. 2005;20(1):27-37.

[3] Miyamoto M, et al. Sleep. 2004;27(7):1319-1325.