Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders

Abstract

An estimated one-third of the general population is affected by insomnia, and this number is increasing due to more stressful working conditions and the progressive aging of society. However, current treatment of insomnia with hypnotics, gamma-aminobutyric acid A (GABA(A)) receptor modulators, induces various side effects, including cognitive impairment, motor disturbance, dependence, tolerance, hangover, and rebound insomnia. Ramelteon (Rozerem; Takeda Pharmaceutical Company Limited, Osaka, Japan) is an orally active, highly selective melatonin MT(1)/MT(2) receptor agonist. Unlike the sedative hypnotics that target GABA(A) receptor complexes, ramelteon is a chronohypnotic that acts on the melatonin MT(1) and MT(2) receptors, which are primarily located in the suprachiasmatic nucleus, the body's "master clock." As such, ramelteon possesses the first new therapeutic mechanism of action for a prescription insomnia medication in over three decades. Ramelteon has demonstrated sleep-promoting effects in clinical trials, and coupled with its favorable safety profile and lack of abuse potential or dependence, this chronohypnotic provides an important treatment option for insomnia.

Figure 1

Comparison of chemical structures of melatonin and ramelteon, (S)‐N‐[2‐(1, 6, 7, 8‐tetrahyrdo‐2H‐indeno[4, 5‐b]furan‐8‐yl)ethyl]propionamide.

Figure 2

(A) Effects of ramelteon on sleep and wakefulness in freely moving cats. Each value shows the mean (with standard error) percentage of time spent in the stages of wakefulness, SWS, or REM sleep during each block of 2 h after drug administration. Eight of 14 cats were randomly used in each dose group. *P≤ 0.05, **P≤ 0.01, compared with the vehicle‐treated control (ANOVA). #P≤ 0.05, ##P≤ 0.01, compared with the vehicle‐treated control (paired t‐test with Holm's correction) [49]. (B) Effects of melatonin on sleep and wakefulness in freely moving cats. Each value shows the mean (with standard error) percentage of time spent in the stages of wakefulness, SWS, or REM sleep during each block of 2 h after drug administration. Eight of 14 cats were randomly used in each dose group. *P≤ 0.05, **P≤ 0.01, compared with the vehicle‐treated control (ANOVA). #P≤ 0.05, ##P≤ 0.01, compared with the vehicle‐treated control (paired t‐test with Holm's correction) [49].

Figure 2

(A) Effects of ramelteon on sleep and wakefulness in freely moving cats. Each value shows the mean (with standard error) percentage of time spent in the stages of wakefulness, SWS, or REM sleep during each block of 2 h after drug administration. Eight of 14 cats were randomly used in each dose group. *P≤ 0.05, **P≤ 0.01, compared with the vehicle‐treated control (ANOVA). #P≤ 0.05, ##P≤ 0.01, compared with the vehicle‐treated control (paired t‐test with Holm's correction) [49]. (B) Effects of melatonin on sleep and wakefulness in freely moving cats. Each value shows the mean (with standard error) percentage of time spent in the stages of wakefulness, SWS, or REM sleep during each block of 2 h after drug administration. Eight of 14 cats were randomly used in each dose group. *P≤ 0.05, **P≤ 0.01, compared with the vehicle‐treated control (ANOVA). #P≤ 0.05, ##P≤ 0.01, compared with the vehicle‐treated control (paired t‐test with Holm's correction) [49].

Figure 3

Effects of ramelteon on latency to sleep onset in freely moving monkeys. Each value shows the mean latency ± SE to each light sleep (LS) and SWS at doses of 0.003 (A), 0.03 (B), and 0.3 mg/kg, p.o. (C). Six monkeys were used in each group. *P ≤ 0.05, **P ≤ 0.01, compared with vehicle‐treated controls [paired t test with Holm correction, 103].

Figure 4

Effects of melatonin on latency to sleep onset in freely moving monkeys. Each value shows the mean latency ± SE to light sleep (LS) and SWS at doses of 0.3 (A), 1 (B), and 3 mg/kg (C). Six or seven monkeys were used in each group. **P ≤ 0.01 compared with the control treated vehicle [paired t test with Holm correction, 103].

Figure 5

Effects of zolpidem on latency to sleep onset in freely moving monkeys. Each value shows the mean latency ± standard error to light sleep (LS) and SWS at doses of 1 (A), 3 (B), and 10 or 30 mg/kg, p.o. (C). Four monkeys were used in each group.

Figure 6

Typical electroencephalographic (EEG) spectra and fast Fourier transform (FFT) analysis in freely moving monkey when treated with ramelteon (0.3 mg/kg, p.o.), melatonin (1 mg/kg, p.o.), and zolpidem (30 mg/kg, p.o.). Typical samples were selected during non‐REM sleep. EEG, electro‐oculogram (EOG) and electromyographic (EMG) activities were recorded [103].

Figure 7

Effects of ramelteon on reentrainment of running‐wheel activity rhythm following an 8‐hour phase advance. Running‐wheel activity in the subjective night as a percentage of total activity in 24 hours is shown with standard error. Ramelteon or vehicle was administered 5–30 min before lights out of the new light‐dark cycle for 14 days starting the day of the phase‐shift. Arrows and black bars show the phase‐shift and the vehicle or ramelteon treatment periods [36].

Figure 8

Effects of ramelteon, melatonin, diazepam, and triazolam on the Morris water maze task in rats. Each value shows the mean time to find the platform submerged in the water (A, B, C, D). *P≤ 0.025, compared with the respective vehicle control group [one‐tailed Williams test, 36].

Figure 9

Percentage of mice failing the rota‐rod performance test after administration of ramelteon (A), melatonin (B), N‐acetyl‐5‐HT (C), or diazepam (D) at the indicated doses. Twelve mice were used in each group. **P≤ 0.01, compared with the control group treated with vehicle (chi‐square test with Holm's correction) [81].

Figure 10

Percentage of mice failing the rota‐rod performance test after administration of diazepam alone or diazepam in combination with ramelteon (A), melatonin (B), N‐acetyl‐5‐HT (C) at the indicated doses. Twelve mice were used in each group. *P≤ 0.05 **P≤ 0.01, compared with the control group treated with vehicle (chi‐square test with Holm's correction) [53].

Figure 11

Effect of ramelteon on place preference in rats. Increase in time spent in the compound‐associated compartment in the conditioned place‐preference tests in rats in the experiment 1 (A and C) and experiment 2 (B). The numbers of rats used are shown in parentheses. Vehicle groups in panels A and B are identical. *P≤ 0.05, compared with the value at the preconditioning phase (paired t‐test) [79].

Figure 12

Metabolic pathway of ramelteon in humans. Ramelteon is extensively metabolized, primarily by carboxylation and stereoselective hydroxylation. The major metabolite of ramelteon in serum is the monohydroxylated metabolite, M‐II.

Figure 13

Effects of ramelteon on sleep latency in patients with chronic insomnia under placebo‐controlled, double‐blind, randomized, 5‐period crossover study. All data are shown as the least square means. ***P≤ 0.001, compared with placebo [78].

Figure 14

Latency to persistent sleep and total sleep time, as measured by PSG, with ramelteon 8 mg, ramelteon 16 mg, and placebo at weeks 1, 3, and 5 (A and B). Subjective sleep latency and total sleep time, as measured by the post‐sleep questionnaire (C and D). For comparisons between ramelteon dose and placebo, *P≤ 0.05, **P≤ 0.01, and ***P≤ 0.001 [68].

Figure 15

Effects of ramelteon on patient‐reported sleep latency in older adults with chronic insomnia. Patients include older adults (≥65 years; n = 829) with chronic insomnia. Placebo, ramelteon 4 mg, or ramelteon 8 mg was taken nightly for 5 weeks, and patient‐reported sleep data were the collected sleep diaries. *P≤ 0.05, **P≤ 0.01, compared with the placebo control [87].