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Polygraphic Recording Procedure for Measuring Sleep in Mice
Published on: January 25, 2016
Pharmacological characterization of M-II, the major human metabolite of ramelteon
Keiji Nishiyama1, Hisao Nishikawa, Koki Kato
1CNS Drug Discovery Unit, Takeda Pharmaceutical Company Ltd., Fujisawa, Japan.
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 (MT1 or MT2) revealed that M-II binds melatonin receptors with lower affinity (Ki: 114 and 566 pmol/l for MT1 and MT2, respectively) and has lower potency (IC50: 208 and 1,470 pmol/l for MT1 and MT2, 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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