Pharmacological characterization of M-II, the major human metabolite of ramelteon

Pharmacology. 2014;93(3-4):197-201. doi: 10.1159/000362459. Epub 2014 Jun 6.


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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • CHO Cells
  • Cats
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Female
  • Half-Life
  • Humans
  • Hypnotics and Sedatives / administration & dosage
  • Hypnotics and Sedatives / pharmacology*
  • Indenes / administration & dosage
  • Indenes / metabolism
  • Indenes / pharmacology*
  • Inhibitory Concentration 50
  • Male
  • Receptor, Melatonin, MT1 / agonists*
  • Receptor, Melatonin, MT1 / metabolism
  • Receptor, Melatonin, MT2 / agonists*
  • Receptor, Melatonin, MT2 / metabolism
  • Sleep / drug effects


  • Hypnotics and Sedatives
  • Indenes
  • Receptor, Melatonin, MT1
  • Receptor, Melatonin, MT2
  • ramelteon