Ramelteon metabolite M-II

Ramelteon metabolite M-II is the major metabolite of Ramelteon, with IC₅₀s of 208 pM, 1470 pM for human melatonin receptors (MT₁ or MT₂). Ramelteon is a selective melatonin agonist. In Vitro: The affinity of Ramelteon metabolite M-II (M-II) for MT₁ receptors is 10- and 2.5-fold lower than that of ramelteon and melatonin, respectively. Likewise, the affinity of M-II for MT₂ receptors is approximately 5- and 1.5-fold lower than that of ramelteon and melatonin, respectively. Ramelteon metabolite M-II exhibits no affinity for quinone reductase 2 at concentrations up to 10 μM. Moreover, the selectivity of Ramelteon metabolite M-II for melatonin receptors relative to 215 targets including other receptors, transporters, ion channels and enzymes is investigated. Ramelteon metabolite M-II shows no significant affinities and activities for the other targets, except for the 5-HT_2B receptor, for which the Ki value was 1.75±0.23 μM. The potency of Ramelteon metabolite M-II for MT₁ receptors is approximately 17- and 4.3-fold lower than that of ramelteon and melatonin, respectively. Similarly, the potency of Ramelteon metabolite M-II for MT₂ receptors is approximately 28- and 1.6-fold lower than that of ramelteon and melatonin, respectively^[1]. In Vivo: Ramelteon metabolite M-II (1 mg/kg) significantly increases NREM sleep (F_1,7=96.3, p<0.01) and significantly decreases wakefulness (F_1,7=56.7, p<0.01). Moreover, a lower dose of M-II (0.1 mg/kg) yield similar results (NREM, F_1,7=121.9, p<0.01; wakefulness, F_1,7=87.0, p<0.01), and decreased wakefulness is sustained for 6 h after the administration of either dose. After the administration of 0.01 mg/kg Ramelteon metabolite M-II, only NREM sleep is significantly increased (F_1,7=10.5, p< 0.05). No significant differences in REM sleep are observed after the administration of M-II at any of the doses tested in this study^[1].