benzofurans and ramelteon

Depression has become one of the most commonly prevalent neuropsychiatric disorders, and the main characteristics of depression are sleep disorders and melatonin secretion disorders caused by circadian rhythm disorders. Abnormal endogenous melatonin alterations can contribute to the occurrence and development of depression. However, molecular mechanisms underlying this abnormality remain ambiguous. The present review summarizes the mechanisms underlying the antidepressant effects of melatonin, which is related to its functions in the regulation of the hypothalamic-pituitary-adrenal axis, inhibition of neuroinflammation, inhibition of oxidative stress, alleviation of autophagy, and upregulation of neurotrophic, promotion of neuroplasticity and upregulation of the levels of neurotransmitters, etc. Also, melatonin receptor agonists, such as agomelatine, ramelteon, piromelatine, tasimelteon, and GW117, have received considerable critical attention and are highly implicated in treating depression and comorbid disorders. This review focuses on melatonin and various melatonin receptor agonists in the pathophysiology and treatment of depression, aiming to provide further insight into the pathogenesis of depression and explore potential targets for novel agent development.

Topics: Animals; Antidepressive Agents; Antioxidants; Benzofurans; Chronobiology Disorders; Cyclopropanes; Depression; Humans; Hypothalamo-Hypophyseal System; Indenes; Melatonin; Pituitary-Adrenal System; Receptors, Melatonin; Sleep Wake Disorders

To investigate the efficacy of exogenous administration of melatonin and melatonin receptor agonists for the improvement of delirium, sleep, and other clinical outcomes of subjects in the intensive care unit (ICU). We carefully searched three electronic databases, i.e., Pubmed/Medline, Embase, and Cochrane library, to retrieve randomized controlled trials (RCTs) administrating melatonin or melatonin receptor agonists to adult subjects admitted to the ICU. Useful data such as the prevalence of delirium, duration of sleep, number of awakenings per night, duration of mechanical ventilation, and ICU stay as well as in-ICU mortality were extracted and pooled by using a random effect model. Eight RCTs were included in the qualitative analysis. Administration of exogenous melatonin and melatonin receptor agonists was associated with a trend towards elongated duration of sleep (pooled weighted mean difference/WMD = 0.43; 95% confidence intervals/CIs, - 0.02~0.88, p = 0.063) and could decrease the number of awakenings per night (pooled WMD = - 2.03; 95% CIs, - 3.83~- 0.22, p = 0.028). Meanwhile, participants in the treatment group showed a significantly reduced prevalence of delirium (pooled risk ratio/RR = 0.49; 95% CIs, 0.28~0.88, p = 0.017) and duration of ICU stay (pooled WMD = - 0.32; 95% CI, - 0.56~- 0.07, p = 0.002) in comparison with those in the control group. Exogenous administration of melatonin and melatonin receptor agonists could improve the sleep of subjects in the intensive care units, which may play an important role in decreasing the prevalence of delirium and shortening duration of ICU stay.

Topics: Adult; Benzofurans; Case-Control Studies; Correlation of Data; Cross-Sectional Studies; Cyclopropanes; Delirium; Hospital Mortality; Humans; Indenes; Intensive Care Units; Length of Stay; Melatonin; Randomized Controlled Trials as Topic; Receptors, Melatonin; Respiration, Artificial; Risk Factors; Sleep; Sleep Wake Disorders; Treatment Outcome; Wakefulness

Geriatric patients often experience insomnia because of physiological and neurological changes that occur during the aging process. Use of benzodiazepines, nonbenzodiazepine hypnotics, and diphenhydramine for the treatment of insomnia pose an increased risk of cognitive impairment, falls, and fractures in this patient population. Therapeutic alternatives approved by the Food and Drug Administration include suvorexant, doxepin, ramelteon, and tasimelteon, which have shown efficacy and safety in various studies. This paper explores and outlines the available safety and efficacy data associated with these medications and reviews their potential place in therapy in treating insomnia in the geriatric population.

Topics: Aged; Aged, 80 and over; Azepines; Benzofurans; Cyclopropanes; Doxepin; Humans; Hypnotics and Sedatives; Indenes; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Triazoles

Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD.

Topics: Antipsychotic Agents; Benzofurans; Bipolar Disorder; Circadian Rhythm; Cyclopropanes; Humans; Inappropriate Prescribing; Indenes; Melatonin; Off-Label Use; Patient Safety; Practice Patterns, Physicians'; Receptors, Melatonin; Risk Assessment; Risk Factors; Sleep; Treatment Outcome

Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, agomelatine and tasimelteon) have recently become available for the treatment of insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy and safety profiles of these compounds in the treatment of the indicated disorders are reviewed. Accumulating evidence indicates that sleep-wake disorders and co-existing medical conditions are mutually exacerbating. This understanding has now been incorporated into the new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Therefore, when evaluating the risk/benefit ratio of sleep drugs, it is pertinent to also evaluate their effects on wake and comorbid condition. Beneficial effects of melatonin receptor agonists on comorbid neurological, psychiatric, cardiovascular and metabolic symptomatology beyond sleep regulation are also described. The review underlines the beneficial value of enhancing physiological sleep in comorbid conditions.

Topics: Acetamides; Animals; Benzofurans; Clinical Trials as Topic; Cyclopropanes; Humans; Hypnotics and Sedatives; Indenes; Melatonin; Neurodegenerative Diseases; Receptors, Melatonin; Sleep Wake Disorders

The various physiological actions of the neurohormone melatonin are mediated mainly by two G-protein-coupled MT(1) and MT(2) receptors. The melatoninergic drugs on the market, ramelteon and agomelatine, as well as the most advanced drug candidates under clinical evaluation, tasimelteon and PD-6735, are high-affinity nonselective MT(1) and MT(2) agonists. However, exploring the exact physiological role of the MT(1) and MT(2) melatonin receptors requires subtype selective MT(1) and MT(2) ligands. This review covers novel melatoninergic agonists and antagonists published since 2010, focusing on high-affinity and subtype selective agents. Additionally, compounds not mentioned in the previous review articles and ligands selective for the MT(3) binding site are included.

Topics: Acetamides; Animals; Benzofurans; Cyclopropanes; Humans; Indenes; Molecular Structure; Receptors, Melatonin; Structure-Activity Relationship

Current pharmacological treatment of insomnia involves the use of sedative-hypnotic benzodiazepine and non-benzodiazepine drugs. Although benzodiazepines improve sleep, their multiple adverse effects hamper their application. Adverse effects include impairment of memory and cognitive functions, next-day hangover and dependence. Non-benzodiazepines are effective for initiating sleep but are not as effective as benzodiazepines for improving sleep quality or efficiency. Furthermore, their prolonged use produces adverse effects similar to those observed with benzodiazepines. Inasmuch as insomnia may be associated with decreased nocturnal melatonin, administration of melatonin is a strategy that has been increasingly used for treating insomnia. Melatonin can be effective for improving sleep quality without the adverse effects associated with hypnotic-sedatives. Ramelteon, a synthetic analog of melatonin which has a longer half life and a stronger affinity for MT1 and MT2 melatonergic receptors, has been reportedly effective for initiating and improving sleep in both adult and elderly insomniacs without showing hangover, dependence, or cognitive impairment. Insomnia is also a major complaint among patients suffering from depressive disorders and is often aggravated by conventional antidepressants especially the specific serotonin reuptake inhibitors. The novel antidepressant agomelatine, a dual action agent with affinity for melatonin MT1 and MT2 receptors and 5-HT2c antagonistic properties, constitutes a new approach to the treatment of major depressive disorders. Agomelatine ameliorates the symptoms of depression and improves the quality and efficiency of sleep. Taken together, the evidence indicates that MT1/MT2 receptor agonists like ramelteon or agomelatine may be valuable pharmacological tools for insomnia and for depression-associated insomnia.

Topics: Acetamides; Animals; Benzodiazepines; Benzofurans; Clinical Trials as Topic; Cyclopropanes; Depressive Disorder; Humans; Hypnotics and Sedatives; Indenes; Indoles; Melatonin; Sleep Initiation and Maintenance Disorders

The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials.

Topics: Acetamides; Animals; Benzofurans; Circadian Rhythm; Cyclopropanes; Humans; Hypnotics and Sedatives; Indenes; Melatonin; Sleep Initiation and Maintenance Disorders

Traveling through several time zones results in a constellation of symptoms known as jet lag. These include reduced alertness, daytime fatigue, loss of appetite, reduced cognitive skills, and disruption of the sleep/wake cycle. In susceptible air travel passengers, jet lag may exacerbate affective illness and result in psychiatric morbidity. Dysregulation of circadian rhythms and melatonin secretion represent the common underlying factor in jet lag and other circadian disorders. Recent studies have established the effectiveness of strategically timed administration of melatonin and appropriate timed exposure to environmental schedules including light in counteracting the dysregulation (chronobiologic actions). With the introduction of melatonergic agonists such as ramelteon and tasimelteon, which have both a stronger affinity for MT₁ and MT₂ melatonin receptors and a longer half-life, new therapeutic options now exist for treating the sleep disturbances associated with jet lag. The melatonin analogs are unique inasmuch as they can also enhance daytime alertness. The recently introduced melatonergic antidepressant agomelatine, which has established its supremacy over other antidepressants in having a significant chronobiologic activity, represents a good choice for treating depressive symptoms that are associated with jet lag.

Topics: Acetamides; Benzofurans; Central Nervous System Depressants; Cyclopropanes; Depressive Disorder; Humans; Indenes; Jet Lag Syndrome; Melatonin; Sleep Disorders, Circadian Rhythm

The pineal hormone melatonin is able to shift the timing of circadian rhythms, including the sleep-wake cycle, and to promote sleep. Melatonin agonists with similar properties have therapeutic potential for the treatment of circadian rhythm sleep disorders. Depression is specifically targeted by agomelatine, which is also a serotonin-2C (5-HT(2C)) antagonist.

Topics: Acetamides; Benzofurans; Cyclopropanes; Drug Administration Schedule; Humans; Indenes; Melatonin; Receptors, Melatonin