Melatonin Receptor Agonist Ramelteon Research Articles

Melatonin and melatonin receptor agonists in the treatment of nocturia: A systematic review.

Causes of nocturia may extend beyond primary bladder pathology and it has been commonly associated as a side effect of sleep disorders. This has led to the study of melatonin and melatonin receptor agonists as a primary treatment for nocturia hypothesized to be secondary to sleep disorders. We aim to systematically review the efficacy and reported safety of melatonin and melatonin receptor agonists in the treatment of nocturia. A search strategy of EMBASE and Pubmed/Medline databases was utilized to identify eligible studies. Two thousand and twenty-eight unique references were identified in concordance with the Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines for systematic reviews, of which nine papers met the inclusion criteria. The Cochrane Collaboration risk of bias criteria in the open label and nonplacebo studies was used to assess bias. The nine studies identified included 3 randomized double-blinded placebo-controlled trials, 2 randomized non-placebo trial, and 4 prospective open-label trials. Three utilized the melatonin-receptor agonist ramelteon (8 mg) and six utilized melatonin (four 2 mg extended release, two 2 mg normal release). Nocturia improved in 8 studies varying from moderate to low efficacy related to reduction in nocturia episodes. Five studies evaluated sleep parameters finding improvement in both nocturia and sleep quality. Male subjects represented 76.8% of 371 total subjects in prospective and randomized trials. Ramelteon and melatonin were both reported as well tolerated during nocturia treatment. A meta-analysis was not able to be performed due to the heterogeneity of bladder diagnoses. At this time, there is insufficient evidence to routinely recommend melatonin as an effective treatment for nocturia given the limitations of current clinical studies. Randomized placebo-controlled trials and prospective open label studies in non-neurogenic populations report a trend towards nocturia improvement with good tolerability and rare side effects. Therefore, further larger scale randomized trials with focused urologic diagnoses in well-characterized patient populations are warranted.

Effects of melatonin on phosphorylation of memory-related proteins in the hippocampus and the perirhinal cortex in male mice.

We recently demonstrated that a single post-training administration of either melatonin, an MT1/MT2 melatonin receptor agonist ramelteon, or a brain melatonin metabolite N1-acetyl-5-methoxyquinuramine (AMK) enhanced object recognition memory. The present study aims to investigate the effects of melatonin, ramelteon, and AMK on relative phosphorylation levels of memory-related proteins in order to explore candidate signaling pathways associated with the receptor-mediated and nonreceptor-mediated memory-enhancing effects of melatonin. We first confirmed that post-training administration of either melatonin, ramelteon, or AMK at 1 mg/kg promoted long-term memory formation, using the novel object recognition task. Next, the effects of the same doses of these drugs on relative phosphorylation levels of the extracellular signal-regulated kinase (ERK) and calcium/calmodulin-dependent kinases (CaMKs) in the hippocampus and the perirhinal cortex (PRC) were examined by western blot analysis. In the hippocampus, treatment with ramelteon or AMK significantly increased and decreased phosphorylation levels of ERK and cAMP-response element binding protein (CREB) and those of CaMKIIα and β, respectively. In the PRC, phosphorylation levels of ERK and those of CaMKIIβ were significantly increased by both ramelteon and AMK and by ramelteon, respectively. Neither ramelteon nor AMK altered the phosphorylation levels of CaMKIV in either hippocampus or PRC. These results suggest that melatonin may be involved in promoting the formation of long-term object recognition memory in a similar, if not identical, manner by modulating the phosphorylation levels of memory-related proteins such as ERK, CaMKIIs, and CREB in both receptor-mediated and nonreceptor-mediated signaling pathways.

Evaluation of the Anxiolytic Effect of Ramelteon in Various Rat Models of Anxiety.

Background Melatonin was found to have anxiolytic properties in several animal and human studies. The melatonin receptor agonist ramelteon might also have a similar anxiolytic action. Objectives The objective of the study was to evaluate the effect of ramelteon in various rat models of anxiety and to explore the possible mechanism of action. Methods The anxiolytic effect was compared between the control group, diazepam group (1 mg/kg and 0.5 mg/kg), and ramelteon group (0.25 mg/kg, 0.5 mg/kg, and1 mg/kg) by an elevated plus maze, light-dark box, hole board apparatus, and open field test in Sprague Dawley rats. Antagonists flumazenil, picrotoxin, and Luzindole were used to explore the possible mechanism of action of ramelteon if it showed an anxiolytic property. Results Ramelteon as a standalone drug did not show an anxiolytic effect. However, a combination of ramelteon (1 mg/kg) and diazepam (0.5 mg/kg) showed an anxiolytic effect. Conclusion Further studies can evaluate the use of a fixed-dose combination of ramelteon and already-approved anxiolytic drugs to reduce the dose of the latter.

Modulatory effect of n-3 polyunsaturated fatty acids on depressive-like behaviors in rats with chronic sleep deprivation: potential involvement of melatonin receptor pathway and brain lipidome.

Clinical evidence suggests that a bidirectional relationship is present between sleep loss and psychiatric disorders. Both melatonin receptor agonist ramelteon (RMT) and n-3 polyunsaturated fatty acids (n-3 PUFAs) exhibit antidepressant effects, while their underlying molecular mechanisms might be different. Thus, the present study aims to investigate the add-on effects and possible mechanisms of how RMT and different n-3 PUFAs modulate the melatonin receptor pathway as well as brain lipidome to ameliorate the neuropsychiatric behaviors displayed in rats under chronic sleep deprivation. Thirty-one 6-week-old male Wistar rats were divided into five groups: control (C), sleep deprivation (S), sleep deprivation treated with RMT (SR), sleep deprivation treated with RMT and eicosapentaenoic acid (C20:5n-3, EPA) (SRE), and sleep deprivation treated with RMT and docosahexaenoic acid (C22:6n-3, DHA) (SRD) groups. The results reveal that RMT plus EPA alleviated depressive-like behavior when the rats were subjected to the forced swimming test, whereas RMT plus DHA alleviated anxiety-like behavior when the rats were subjected to the elevated plus maze test. The results of a western blot analysis further revealed that compared with the rats in the S group, those in the SRE and SRD groups exhibited a significantly increased expression of MT2 in the prefrontal cortex, with greater benefits observed in the SRE group. In addition, decreased BDNF and TrkB expression levels were upregulated only in the SRE group. Lipidomic analysis further revealed possible involvement of aberrant lipid metabolism and neuropsychiatric behaviors. RMT plus EPA demonstrated promise as having the effects of reversing the levels of the potential biomarkers of depressive-like behaviors. RMT plus EPA or DHA could ameliorate depressive- and anxiety-like behaviors in sleep-deprived rats through the alteration of the lipidome and MT2 receptor pathway in the brain, whereas EPA and DHA exerted a differential effect.

1230: INTENSIVE CARE UNIT USE OF MELATONIN RECEPTOR AGONISTS IMPROVES OUTCOMES IN SEPSIS PATIENTS

Introduction: Delirium aggravates the morbidity and mortality of sepsis patients. Melatonin, the endogenous circadian rhythm regulating hormone, can decrease delirium. Also, melatonin possesses anti-oxidation and anti-inflammation capacity. Of note, the effects of melatonin can be activated by melatonin receptor agonists (such as tasimelteon and ramelteon). Thus, we hypothesized that using melatonin receptor agonists may improve the outcomes of sepsis patients in intensive care unit (ICU). To elucidate further on this issue, we conducted this retrospective study analyzing data retrieved from the Medical Information Mart for Intensive Care (MIMIC) IV database. Methods: Data from the MIMIC IV database were retrieved and analyzed. Only sepsis patients admitted to ICU were included. Patients who stayed in ICU less than 3 days were excluded. Between-group differences in the in-hospital mortality and overall mortality rates were analyzed using the Chi square test. The impacts of ICU use of melatonin receptor agonists on in-hospital mortality and overall mortality in sepsis patients were analyzed using logistic regression analysis. Results: A total of 3943 sepsis patients were included. Among them, 3.78% received melatonin receptor agonists (the Melatonin group, n=149), and ramelteon was the only melatonin receptor agonist these patients received. In addition, 96.22% of the included sepsis patients did not use melatonin receptor agonists (the non-Melatonin group, n=3794) during the entire course of hospitalization. In-hospital mortality rate (20.8% versus 31.0%, p=0.008) and the overall mortality rate (27.5% versus 39.3%%, p=0.004) in the Melatonin group were significantly lower than in the non-Melatonin group. Logistic regression analysis revealed that Melatonin group were associated with significantly lower risks of in-hospital mortality (odd’s ratio [OR]: 0.59, 95% confidence intervals [CI]: 0.39~0.88, p=0.009) and overall mortality (OR: 0.59, 95% CI: 0.41~0.84, p=0.004) comparing to non-Melatonin group. After adjusting for age and gender, the trend remained the same (in-hospital mortality: OR: 0.56, 95% CI: 0.37~0.84, p=0.005; overall mortality: OR: 0.56, 95% CI: 0.38~0.80, p=0.002). Conclusions: ICU use of melatonin receptor agonist ramelteon associated with outcome improvements in sepsis patients.

Melatonin and risk of mortality in subjects with aneurysmal subarachnoid hemorrhage

BackgroundDelayed cerebral ischemia (DCI) is a cause of morbidity associated with aneurysmal subarachnoid hemorrhage (aSAH). Neuroinflammation contributes to the development of DCI. Melatonin is a sleep-promoting hormone known to have cerebral anti-inflammatory properties. We hypothesized that synthetic melatonin (or the selective melatonin receptor agonist ramelteon) incidentally prescribed to improve sleep may lower the incidence of DCI among hospitalized aSAH patients. MethodsSubjects with a Hunt and Hess Grade I-III were identified from a data registry involving all aSAH patients admitted to our hospital between January 2015 and September 1, 2018. A cohort of patients who received either melatonin or ramelteon during their hospitalization was compared to a matched cohort that did not receive these drugs. The primary endpoint was incidence of DCI. Secondary outcomes included modified Rankin score (mRS) at discharge, discharge destination, and mortality at 6 weeks from discharge. The two groups were compared using univariate analysis. P < 0.05 was considered significant. ResultsThere was no significant difference in the incidence of DCI (15.8% vs. 16.9%, p = 1), discharge mRS (mRS 0–3: 51.3% vs. 45.1%, p = 0.59), discharge disposition (Home: 43.6% vs. 44.4, p = 0.47), or mortality (0% vs. 9.2%; p = 0.074) between the melatonin/ramelteon and non-melatonin groups. ConclusionThe use melatonin had no effect on DCI but may improve mortality in aSAH subjects. Prospective studies using a larger cohort are warranted to validate these findings.

Pharmacotherapies for sleep disturbances in dementia.

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The Melatonin Receptor Agonist Ramelteon Induces Cardioprotection that Requires MT2 Receptor Activation and Release of Reactive Oxygen Species

PurposeThe melatonin receptor (MT) agonist ramelteon has a higher affinity to MT1 than for MT2 receptors and induces cardioprotection by involvement of mitochondrial potassium channels. Activation of mitochondrial potassium channels leads to release of free radicals. We investigated whether (1) ramelteon-induced cardioprotection is MT2 receptor specific and (2) if free radicals are involved in ramelteon-induced cardioprotection.MethodsHearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia hearts were perfused with ramelteon (Ram) with or without the MT2 receptor inhibitor 4-phenyl-2-propionamidotetralin (4P-PDOT+Ram, 4P-PDOT). In subsequent experiments, ramelteon was administered together with the radical oxygen species (ROS) scavenger N-2-mercaptopropionylglycine (MPG+Ram). To determine whether the blockade of ramelteon-induced cardioprotection can be restored, we combined ramelteon and MPG with mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A (CsA) at different time points. Infarct size was determined by triphenyltetrazolium chloride (TTC) staining.ResultsRamelteon-induced infarct size reduction was completely blocked by 4P-PDOT and MPG. Ramelteon and MPG combined with CsA before ischemia were not cardioprotective but CsA at the onset of reperfusion could restore infarct size reduction.ConclusionsThis study shows for the first time that despite the higher affinity to MT1 receptors, (1) ramelteon-induced cardioprotection involves MT2 receptors, (2) cardioprotection requires ROS release, and (3) inhibition of the mPTP can restore infarct size reduction.

A simple method using anesthetics to test effects of sleep-inducing substances in mice

We investigated the effects of sleep-inducing agents with different mechanisms of action on the loss of the righting reflex induced by isoflurane or a mixture of medetomidine, midazolam, and butorphanol (MMB), followed by atipamezole reversal. Chlorpromazine and brotizolam delayed recovery from both types of anesthesia, whereas the melatonin receptor agonist ramelteon had no effect. The orexin receptor antagonist suvorexant delayed recovery from anesthesia only in the case of MMB, while the sleep-promoting supplement glycine only delayed recovery in the case of isoflurane. These results suggest that the simple comparison method is applicable for testing substances expected to exert sleep-inducing effects.

Melatonin Receptor Agonist Ramelteon Reduces Ischemia-Reperfusion Injury Through Activation of Mitochondrial Potassium Channels.

Activation of melatonin receptors induces cardioprotection. Mitochondrial potassium channels (mKCa and mKATP) are involved in the signaling cascade of preconditioning. The melatonin receptor agonist ramelteon is an approved oral medication for treatment of insomnia, but nothing is known about possible cardioprotective properties. We investigated whether (1) ramelteon induces cardioprotection mediated by the melatonin receptor; (2) this effect is concentration-dependent; and (3) mKCa and/or mKATP channels are critically involved in ramelteon-induced cardioprotection. Hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with Krebs-Henseleit buffer at a constant pressure of 80 mm Hg. All hearts were subjected to 33 minutes of global ischemia and 60 minutes of reperfusion. Before, ischemic hearts were perfused with different concentrations of ramelteon (0.01-5 μM) for determination of a concentration-effect curve. In subsequent experiments, the lowest protective concentration of ramelteon was administered together with paxilline (mKCa channel inhibitor) and 5-hydroxydecanoate (mKATP channel inhibitor). To determine whether the reduction of ischemia and reperfusion injury by ramelteon is mediated by melatonin receptor, we combined ramelteon with luzindole, a melatonin receptor antagonist. Infarct size was determined by triphenyltetrazolium chloride staining. In control animals, infarct size was 58% ± 6%. Ramelteon in a concentration of 0.03 µM reduced infarct size to 28% ± 4% (P < 0.0001 vs. Con). A lower concentration of ramelteon did not initiate cardioprotection, and higher concentrations did not further decrease infarct size. Paxilline, 5-hydroxydecanoate, and luzindole completely blocked the ramelteon-induced cardioprotection. This study shows for the first time that (1) ramelteon induces cardioprotection through melatonin receptor; (2) the effect is not concentration-dependent; and (3) activation of mKCa and mKATP channels is involved.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Efficacy and safety of sublingual ramelteon as an adjunctive therapy in the maintenance treatment of bipolar I disorder in adults: A phase 3, randomized controlled trial

BackgroundThe optimal long-term management strategy for bipolar I disorder patients is not yet established. Evidence supports the rationale for circadian rhythm regulation to prevent mood episode relapse in bipolar patients. This study evaluated the efficacy and safety of a new sublingual formulation of the melatonin receptor agonist ramelteon (ramelteon SL) as adjunctive therapy in the maintenance treatment of bipolar I patients. MethodsIn a double-blinded trial in the United States and Latin America, adult bipolar I disorder patients stable for ≥ 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1mg (n = 164), 0.4mg (n = 160), or 0.8mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power ≥ 30% compared with placebo. ResultsNo significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon. LimitationsA low rate of relapse events precluded detection of any statistically significant difference between groups. ConclusionsThe study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions.

An update of management of insomnia in patients with chronic orofacial pain.

In this review, we discuss the management of chronic orofacial pain (COFP) patients with insomnia. Diagnostic work-up and follow-up routines of COFP patients should include assessment of sleep problems. Management is based on a multidisciplinary approach, addressing the factors that modulate the pain experience as well as insomnia and including both non-pharmacological and pharmacological modalities. Parallel to treatment, patients should receive therapy for comorbid medical and psychiatric disorders, and possible substance abuse that may be that may trigger or worsen the COFP and/or their insomnia. Insomnia treatment should begin with non-pharmacological therapy, to minimize potential side effects, drug interactions, and risk of substance abuse associated with pharmacological therapy. Behavioral therapies for insomnia include the following: sleep hygiene, cognitive behavioral therapy for insomnia, multicomponent behavioral therapy or brief behavioral therapy for insomnia, relaxation strategies, stimulus control, and sleep restriction. Approved U.S. Food and Drug Administration medications to treat insomnia include the following: benzodiazepines (estazolam, flurazepam, temazepam, triazolam, and quazepam), non-benzodiazepine hypnotics (eszopiclone, zaleplon, zolpidem), the melatonin receptor agonist ramelteon, the antidepressant doxepin, and the orexin receptor antagonist suvorexant. Chronic orofacial pain can greatly improve following treatment of the underlying insomnia, and therefore, re-evaluation of COFP is advised after 1month of treatment.

An Open-Labeled Trial of Ramelteon in Idiopathic Rapid Eye Movement Sleep Behavior Disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by REM sleep without atonia and elaborate motor activity in association with dream mentation. The melatonin receptor agonist ramelteon has been documented as being effective in two patients with secondary RBD. However, there are no reports on ramelteon treatment for idiopathic RBD. In an open-labeled trial, we treated 12 consecutive patients with idiopathic RBD for at least 4 w with 8 mg ramelteon given within 30 min before bedtime. Ramelteon treatment did not have a clear effect on REM sleep without atonia or an RBD severity scale measured by video-supported polysomnography. However, clinical assessment using a visual analog scale showed a trend toward significance and there were also definitely positive changes in some individual cases. Ramelteon was well tolerated in most patients, with minor side effects. Considering that ramelteon is associated with few side effects, further study may ascertain whether patients with RBD could be effectively treated by ramelteon, especially when clonazepam may not be suitable due to its side effects. A commentary on this article appears in this issue on page 643.

The Effects of Benzodiazepine and Nonbenzodiazepine Agents, Ramelteon, Low-dose Doxepin, Suvorexant, and Selective Serotonin 5-HT2A Receptor Antagonists and Inverse Agonists on Sleep and Wakefulness

Several agents are known to improve sleep induction and/or maintenance in patients with insomnia disorder. These include the benzodiazepine (BZD) and non-BZD receptor allosteric modulators, the melatonin receptor agonist ramelteon, low-dose doxepin, and suvorexant. One of the drawbacks of the BZDs is their known reduction in both N3 sleep [also known as slow wave sleep or delta sleep and characterized by the occurrence of slow high amplitude delta (0.5–2 Hz) waves] and rapid eye movement (REM) sleep. Low-dose doxepin has shown similar association with decrease in REM sleep. By contrast, suvorexant increases REM sleep. The available evidence tends to indicate that irrespective of their mechanisms of action, the selective serotonin 5-HT2A receptor antagonists and inverse agonists, including volinanserin, pruvanserin, and nelotanserin, when given in isolated administration, increases slow wave sleep in laboratory animals. Wakefulness and REM sleep were decreased in some studies. Moreover, subjects with normal sleep showed significant increase in N3 sleep following the administration of eplivanserin, nelotanerin, and pimavanserin. Nelotanserin has also been shown to augment N3 sleep in patients with chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. Taken together, these evidences suggest that the coadministration of a selective 5-HT2A receptor antagonist or inverse agonist with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with insomnia disorder. Additionally, the 5-HT2A receptor agents may have a potential value for improving the cognition and memory deficits in patients with a chronic insomnia disorder as well as elderly patients who show reductions in N3 sleep.

Novel Developments in the Pharmacological Management of Insomnia

Advances in the basic science of sleep/wake neurophysiology are driving the exploration of new pharmacologic approaches with continued improvement in efficacy and safety.

Chronic Insomnia, Pharmacotherapy and the Cognitive Behavioral Approaches

Insomnia is a common complaint of patients presenting to primary care physician and sleep medicine experts. Approximately 10-20% of the general population worldwide has reported symptoms of chronic insomnia of which 25% have primary insomnia. Insomnia is more prevalent among females and the elderly subjects (over 65 years). Pharmacotherapy for insomnia is mainly focused on hypnotics such as benzodiazepine receptor agonists (BzRAs), antihistamine drugs, tricyclic antidepressants like doxepin, and a melatonin receptor agonist (ramelteon). However, these very often used medications are shown to have potential untoward effects outweighing their benefits in many instances. Once the underlying disorder affecting sleep is appropriately addressed, cognitive behavioral therapy, singly or combined with drug therapy, is demonstrated to be amongst the most efficacious treatment strategies in some cases with refractory insomnia.

Melatonin Receptors Mediate Improvements of Survival in a Model of Polymicrobial Sepsis

Melatonin has been demonstrated to improve survival after experimental sepsis via antioxidant effects. Yet, recent evidence suggests that this protective capacity may also rely on melatonin receptor activation. Therefore, the present study was designed to investigate whether selective melatonin receptor-agonist ramelteon may influence survival and immune response in a model of polymicrobial sepsis in rats, wild-type and melatonin receptor MT1/MT2 double knockout mice. Prospective, randomized, controlled study. University research laboratory. Male Sprague-Dawley rats (200-250 g) and male C3H/HeN wild-type and MT1/MT2 receptor knockout mice (20-22 g). Animals underwent cecal ligation and incision and remained anesthetized for evaluation of survival for 12 hours (rats: n = 15 per group) or 15 hours (mice: n = 10 per group). Analysis of immune response by means of enzyme-linked immunosorbent assay was performed before and 5 hours after cecal ligation and incision (rats only; n = 5 per group). After induction of sepsis, animals were treated IV with vehicle, different doses of melatonin (rats: 0.01/0.1/1.0/10 mg/kg; mice: 1.0 mg/kg), ramelteon, melatonin receptor-antagonist luzindole, ramelteon + luzindole, or melatonin + luzindole (each 1.0 mg/kg). Sham controls underwent laparotomy but not cecal ligation and incision. Compared with vehicle, administration of ramelteon or melatonin significantly improved median survival time in rats (sepsis/melatonin [0.1 mg/kg], 554 min, [1.0 mg/kg] 570 min, [10 mg/kg] 579 min; sepsis/ramelteon, 468 min; each p < 0.001 vs sepsis/vehicle, 303 min) and wild-type mice (sepsis/melatonin, 781 min; sepsis/ramelteon, 701 min; both p < 0.001 vs sepsis/vehicle, 435 min). This effect was completely antagonized by coadministration of luzindole in all groups. Melatonin, ramelteon, or luzindole had no significant effect on survival time in knockout mice. Significantly elevated concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-10 were observed 5 hours after cecal ligation and incision in rats (p < 0.05 vs baseline and corresponding sham); neither ramelteon nor melatonin treatment significantly affected immune response. Melatonin receptors mediate improvements of survival after polymicrobial sepsis in rats and mice; this effect appears to be independent from major alterations of cytokine release.

Melatonin ameliorates Angiotensin II‐induced vascular endothelial damage via its antioxidative properties

Melatonin is well known to have a beneficial effect on the cardiovascular system, but it remains to be elucidated whether melatonin has a therapeutic effect on the vascular damage induced by the potential vasoactive substance angiotensin II (Ang II). In this study, the effects of melatonin on Ang II-induced vascular endothelial damage were investigated. In cultured vascular endothelial cells, Ang II stimulation increased ROS generation and inhibited eNOS phosphorylation (Ser1177), both of which were clearly restored by pretreatment with melatonin. The translocation of p47(phox) subunit of NADPH oxidase from the cytosol to plasma membrane was promoted in Ang II-treated vascular endothelial cells, which was canceled by melatonin pretreatment. In Ang II-infused rats, increased ROS generation in the aortic wall and impaired endothelial function of the aortic ring were observed, which were rescued by coadministration of melatonin. In vasculature, melatonin receptor agonist ramelteon had the antioxidative effect in the same manner as melatonin by itself. These findings suggest that melatonin directly ameliorates Ang II-induced vascular endothelial damage partly via its antioxidative properties, providing with us the potential rationale for clinical application of melatonin to the prevention from cardiovascular diseases.

Synthesis of the melatonin receptor agonist Ramelteon using a tandem C–H activation–alkylation/Heck reaction and subsequent asymmetric Michael addition

An asymmetric synthesis of the melatonin receptor agonist Ramelteon 1 has been achieved, which involved a tandem C–H activation–alkylation/Heck reaction and subsequent highly diastereoselective asymmetric Michael addition to generate the corresponding chiral intermediate, which was readily converted into Ramelteon 1 in 19% overall yield in 15 linear steps.