Dipartimento di Scienze del Farmaco e della Salute, University of Urbino Carlo Bo, Urbino (PU), Italy.
CNS Neurosci Ther. 2011 Dec;17(6):733-41. doi: 10.1111/j.1755-5949.2010.00197.x.
The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT₁ or MT₂ subtype-selective compounds are available up to now. Administration of the MT₂-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT₂ receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT₁ or MT₂ receptors are expected in coming years.
褪黑素（MLT）分泌的昼夜节律性，加上 MLT 受体在视交叉上核中的定位，导致了许多关于 MLT 在调节人类睡眠-觉醒周期和昼夜节律中的作用的研究。尽管人们需要更多地了解 MLT 发挥的各种功能及其作用机制，但已有三种治疗药物（雷美替胺、延长释放 MLT 和阿戈美拉汀）在使用，而 MLT 受体激动剂现在作为治疗睡眠和昼夜节律障碍的新的有前途的治疗选择出现。在这篇综述中，重点介绍了导致 MLT 受体激动剂的药物化学策略，以及支持正在进行临床评估的化合物治疗效果的证据。广泛的临床试验表明，雷美替胺、延长释放 MLT 和他司美琼具有促进睡眠的作用，为失眠和短暂性失眠提供了重要的治疗选择，即使睡眠维持的改善似乎是温和的。阿戈美拉汀有明确的作用，表明这种 MLT 激动剂为治疗抑郁症提供了一个有吸引力的选择，它结合了疗效和良好的副作用特征。尽管有大量高亲和力的非选择性 MLT 受体激动剂，但到目前为止，只有有限的数据涉及 MT₁或 MT₂亚型选择性化合物。给大鼠施用 MT₂ 选择性激动剂 IIK7 已被证明可降低非快速眼动睡眠潜伏期，表明 MT₂ 受体亚型参与 MLT 的急性促睡眠作用；需要严格的临床研究来证明这一假设。预计在未来几年内，将有更多基于选择性激活 MT₁ 或 MT₂ 受体的临床候选药物出现。
