Asymmetric conjugated addition of allylcopper reagents derived from an allyl Grignard reagent and CuBr·Me_2S to chiralα,β-unsaturated N-acyl oxazolidinones has been achieved.The synthetic procedure was applied ...Asymmetric conjugated addition of allylcopper reagents derived from an allyl Grignard reagent and CuBr·Me_2S to chiralα,β-unsaturated N-acyl oxazolidinones has been achieved.The synthetic procedure was applied to the preparation of the key intermediate of the novel nonbenzodiazepine hypnotic drug,ramelteon.展开更多
To examine the efficacy of the melatonin receptor agonist ramelteon for nocturia, it was compared with zolpidem, a conventional non-benzodiazepine hypnotic. A total of 50 patients with nocturia (32 urinations/night) w...To examine the efficacy of the melatonin receptor agonist ramelteon for nocturia, it was compared with zolpidem, a conventional non-benzodiazepine hypnotic. A total of 50 patients with nocturia (32 urinations/night) were enrolled. Subjects assigned odd numbers or even numbers were respectively prescribed 8 mg of ramelteon (n = 27;mean age: 75 years) or 5 mg of zolpidem (n = 23;mean age: 73 years) once a day before sleeping for 4 weeks. The daytime and nighttime frequencies of urination, as well as the results of global self-assessment by the patients, were compared between the two groups before and after 4 weeks of treatment. Both ramelteon and zolpidem caused a significant decrease of nocturia to about once per night after 4 weeks. The global self-assessment rating at 4 weeks was “good” or “fair” for more patients in the zolpidem group than in the ramelteon group, while the rating was “excellent” or “no change” for more patients in the ramelteon group. There were no serious adverse events in either group. Ramelteon was safe and effective for nocturia, achieving similar results to zolpidem. However, responders and non-responders to ramelteon were more clearly distinguished. Ramelteon might be effective for patients with sleep disturbance and nocturia because of low melatonin levels. Therefore, as diagnostic therapy for identification of nocturia caused by sleep disturbance and melatonin deficiency, ramelteon should be administered to patients who do not respond to alpha-1 antagonists and/or anticholinergic agents.展开更多
Melatonin,the hormone of darkness and messenger of the photoperiod,is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ pro...Melatonin,the hormone of darkness and messenger of the photoperiod,is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone's intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo,and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis,hemorrhagic shock,ischemia/reperfusion,and in numerous models of toxic liver injury. Melatonin's influence on hepatic antioxidant enzymes and other potentially relevant pathways,such as nitric oxide signaling,hepatic cytokine and heat shock protein expression,are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection,this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy.展开更多
Melatonin (MEL) has been reported to have acute enhancing effects on some aspects of cognition. Recently, we revealed that N1-acetyl-5-methoxyquinuramine (AMK), a brain metabolite of MEL, is much more potent than MEL ...Melatonin (MEL) has been reported to have acute enhancing effects on some aspects of cognition. Recently, we revealed that N1-acetyl-5-methoxyquinuramine (AMK), a brain metabolite of MEL, is much more potent than MEL in converting short-term memory (STM) to long-term memory (LTM) with a single administration immediately after the acquisition trial of the novel object recognition (NOR) task. These data suggest that the memory-enhancing effects of MEL may be mediated by mechanisms independent of the activation of MEL MT1 and MT2 receptors. In the present study, we examined the contribution of MT1 and MT2 receptor-mediated and non-receptor-mediated mechanisms to the acute memory-enhancing effects of MEL using NOR task. Mice were administered with either MEL, AMK, or a highly selective MT1/MT2 receptor agonist ramelteon (RAM) immediately after the acquisition trial and the effects of varying doses of these drugs on both STM and LTM performance were compared. We found that both AMK and RAM were more potent than MEL in both facilitating STM and promoting LTM formation. We also found that pretreatment with luzindole, a MT1/MT2 receptor antagonist, markedly suppressed only the effects of RAM. These results suggest that acutely administered MEL enhances NOR memory through both MT1 and MT2 receptor-mediated and non-receptor-mediated mechanisms.展开更多
One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings...One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms and changing reproductive hormone levels, circadian rhythm abnormalities, primary insomnia, mood disorders, coexistent medical conditions, and lifestyle. Exogenous melatonin reportedly induces drowsiness and sleep, and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs with prolonged effects and slow-release melatonin preparations have been developed. The melatonergic receptor ramelteon is a selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonist with negligible affinity for other neuronal receptors, including gamma-aminobutyric acid and benzodiazepine receptors. It was found effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT1 and MT2 melatonergic agonism and relatively weak serotonin 5HT2C receptor antagonism, reportedly is effective in the treatment of depression associated insomnia. This article presents the currently available evidence regarding the effects of these compounds on sleep quality and their possible use in menopause associated sleep disturbances.展开更多
基金the Shanghai Municipal Natural Science Foundation(No10ZR1409600)
文摘Asymmetric conjugated addition of allylcopper reagents derived from an allyl Grignard reagent and CuBr·Me_2S to chiralα,β-unsaturated N-acyl oxazolidinones has been achieved.The synthetic procedure was applied to the preparation of the key intermediate of the novel nonbenzodiazepine hypnotic drug,ramelteon.
文摘To examine the efficacy of the melatonin receptor agonist ramelteon for nocturia, it was compared with zolpidem, a conventional non-benzodiazepine hypnotic. A total of 50 patients with nocturia (32 urinations/night) were enrolled. Subjects assigned odd numbers or even numbers were respectively prescribed 8 mg of ramelteon (n = 27;mean age: 75 years) or 5 mg of zolpidem (n = 23;mean age: 73 years) once a day before sleeping for 4 weeks. The daytime and nighttime frequencies of urination, as well as the results of global self-assessment by the patients, were compared between the two groups before and after 4 weeks of treatment. Both ramelteon and zolpidem caused a significant decrease of nocturia to about once per night after 4 weeks. The global self-assessment rating at 4 weeks was “good” or “fair” for more patients in the zolpidem group than in the ramelteon group, while the rating was “excellent” or “no change” for more patients in the ramelteon group. There were no serious adverse events in either group. Ramelteon was safe and effective for nocturia, achieving similar results to zolpidem. However, responders and non-responders to ramelteon were more clearly distinguished. Ramelteon might be effective for patients with sleep disturbance and nocturia because of low melatonin levels. Therefore, as diagnostic therapy for identification of nocturia caused by sleep disturbance and melatonin deficiency, ramelteon should be administered to patients who do not respond to alpha-1 antagonists and/or anticholinergic agents.
基金Supported by (in part) Grants from the European Society of Anesthesiology and the HOMFOR Homburger Forschungsfrderung
文摘Melatonin,the hormone of darkness and messenger of the photoperiod,is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone's intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo,and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis,hemorrhagic shock,ischemia/reperfusion,and in numerous models of toxic liver injury. Melatonin's influence on hepatic antioxidant enzymes and other potentially relevant pathways,such as nitric oxide signaling,hepatic cytokine and heat shock protein expression,are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection,this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy.
文摘Melatonin (MEL) has been reported to have acute enhancing effects on some aspects of cognition. Recently, we revealed that N1-acetyl-5-methoxyquinuramine (AMK), a brain metabolite of MEL, is much more potent than MEL in converting short-term memory (STM) to long-term memory (LTM) with a single administration immediately after the acquisition trial of the novel object recognition (NOR) task. These data suggest that the memory-enhancing effects of MEL may be mediated by mechanisms independent of the activation of MEL MT1 and MT2 receptors. In the present study, we examined the contribution of MT1 and MT2 receptor-mediated and non-receptor-mediated mechanisms to the acute memory-enhancing effects of MEL using NOR task. Mice were administered with either MEL, AMK, or a highly selective MT1/MT2 receptor agonist ramelteon (RAM) immediately after the acquisition trial and the effects of varying doses of these drugs on both STM and LTM performance were compared. We found that both AMK and RAM were more potent than MEL in both facilitating STM and promoting LTM formation. We also found that pretreatment with luzindole, a MT1/MT2 receptor antagonist, markedly suppressed only the effects of RAM. These results suggest that acutely administered MEL enhances NOR memory through both MT1 and MT2 receptor-mediated and non-receptor-mediated mechanisms.
文摘One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms and changing reproductive hormone levels, circadian rhythm abnormalities, primary insomnia, mood disorders, coexistent medical conditions, and lifestyle. Exogenous melatonin reportedly induces drowsiness and sleep, and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs with prolonged effects and slow-release melatonin preparations have been developed. The melatonergic receptor ramelteon is a selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonist with negligible affinity for other neuronal receptors, including gamma-aminobutyric acid and benzodiazepine receptors. It was found effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT1 and MT2 melatonergic agonism and relatively weak serotonin 5HT2C receptor antagonism, reportedly is effective in the treatment of depression associated insomnia. This article presents the currently available evidence regarding the effects of these compounds on sleep quality and their possible use in menopause associated sleep disturbances.
