Ramelteon is a potent, highly selective, and orally active agonist of MT1/MT2. Strikingly, it has the potential for the research of insomnia. And Ramelteon consistently reduces sleep onset after long-term treatment, with no next-morning residual effects or rebound insomnia or withdrawal symptoms upon discontinuation.
Ramelteon is a highly selective melatonin receptor agonist with high affinity for MT1 and MT2 receptors but only negligible affinity for MT3 receptors.
Ramelteon (3-30 mg/kg, p.o.) and melatonin (10-100 mg/kg, p.o.) did not affect learning or memory in rats tested by the water maze task and the delayed match to position task, although diazepam and triazolam impaired both of the tasks. Neither ramelteon (3-30 mg/kg, p.o.) nor melatonin (10-100 mg/kg, p.o.) demonstrated a rewarding property in the conditioned place-preference test, implying that MT1/MT2 receptor agonists have no abuse potential.
Ramelteon significantly decreased wakefulness at doses of 0.001,0.01, and 0.1 mg/kg, increased slow-wave sleep at doses of 0.001, 0.01, and 0.1 mg/kg, and increased rapid eye movement sleep at a dose of 0.1 mg/kg, compared with the vehicle controls, as assessed by analysis of variance. The effects of ramelteon lasted for up to 6 hours when evaluated by reduction of wakefulness. Exogenous melatonin significantly increased slow-wave sleep, but the effect was weaker than ramelteon and lasted for only 2 hours. The lowest doses of ramelteon (0.0001 mg/kg) and melatonin (0.001 mg/kg) had no significant effect on sleep-wakefulness stage.
Ramelteon was more effective than exogenous melatonin in promoting and maintaining sleep in freely moving cats. Based on its unique mechanism of action, ramelteon should be studied further to evaluate its potential for sleep disorders studies.
Keisuke Hirai, et al. Ramelteon (TAK-375) accelerates reentrainment of circadian rhythm after a phase advance of the light-dark cycle in rats. J Biol Rhythms. 2005 Feb;20(1):27-37.
Masaomi Miyamoto, et al. The sleep-promoting action of ramelteon (TAK-375) in freely moving cats. Sleep. 2004 Nov 1;27(7):1319-25.