Abstract
The duration of action of melatonin may be important for improvements in sleep efficiency in insomniacs. Ramelteon, a selective melatonin agonist, is primarily metabolized to the active metabolite M-II, which has a longer half-life and greater systemic exposure than ramelteon. Hence, M-II may contribute significantly to the hypnotic benefits of ramelteon. We assessed the ramelteon-like activity of M-II in vitro and in vivo using cats. Binding and functional studies in Chinese hamster ovary cells expressing human melatonin receptors (MT<sub>1</sub> or MT<sub>2</sub>) revealed that M-II binds melatonin receptors with lower affinity (K<sub>i</sub>: 114 and 566 pmol/l for MT<sub>1</sub> and MT<sub>2</sub>, respectively) and has lower potency (IC<sub>50</sub>: 208 and 1,470 pmol/l for MT<sub>1</sub> and MT<sub>2</sub>, respectively) compared with ramelteon. However, higher M-II doses significantly improved sleep in cats. Thus, M-II may contribute to the clinical efficacy of ramelteon.
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