Ramelteon metabolite M-II is the major Ramelteon metabolite(human melatonin receptors (MT1 or MT2) with IC50s of 208 pM, 1470 pM). Ramelteon is an agonist of selective melatonin.

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. The selectivity of M-II for melatonin receptors relative to 215 targets including other receptors, transporters, ion channels and enzymes is investigated. M-II shows no significant affinities and activities for the other targets, except for the 5-HT2B receptor, for which the Ki value was 1.75±0.23 μM. The potency of M-II for MT1 receptors is approximately 17- and 4.3-fold lower than that of ramelteon and melatonin, respectively. Similarly, the potency of M-II for MT2 receptors is approximately 28- and 1.6-fold lower than that of ramelteon and melatonin, respectively.

Ramelteon metabolite M-II 1 mg/kg significantly increases NREM sleep and significantly decreases wakefulness. Moreover, a lower dose of M-II (0.1 mg/kg) yield similar results (NREM, F1,7=121.9, p<0.01; wakefulness, F1,7=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 M-II, only NREM sleep is significantly increased . No significant differences in REM sleep are observed after the administration of M-II at any of the doses tested in this study.