title: Pharmacological characterization of M-II, the major human metabolite of ramelteon.
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.
authors.affiliation: CNS Drug Discovery Unit, Takeda Pharmaceutical Company Ltd., Fujisawa, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Hisao
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Koki
authors.initials: K
authors.lastname: Kato
authors.forename: Masaomi
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hirai
mesh_terms: D000818:Animals; D016466:CHO Cells; D002415:Cats; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology*; D007192:Indenes / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D044122:Receptor, Melatonin, MT1 / Q000819:agonists* / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000819:agonists* / Q000378:metabolism; D012890:Sleep / Q000187:drug effects
chemical_list: D006993:Hypnotics and Sedatives; D007192:Indenes; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; C495910:ramelteon