Structure-Activity Relationship, Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT-462206: a Potent, Brain-Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist
Structure-Activity Relationship, Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT-462206: a Potent, Brain-Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist
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DOI：
10.1002/cmdc.201402258
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发表时间：
2014-11-01
期刊：
影响因子：
3.4
通讯作者：
Gatfield, John
中科院分区：
文献类型：
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作者：
Boss, Christoph;Roch-Brisbare, Catherine;Gatfield, John
食欲素系统包括两个G蛋白偶联受体，即广泛表达于大脑不同区域的食欲素1和食欲素2受体，以及两种肽激动剂，食欲素A和食欲素B，它们是在下丘脑外侧神经元的一个小集合中产生的。食欲素系统在维持清醒状态中起着重要作用。几种化合物(Almore xant，SB-649868，Suvorexant)已经进入了治疗原发性失眠的高级临床试验。ACT-462206是一种新的、有效的、选择性的双重增食欲素受体拮抗剂(DORA)，它可以抑制增食欲素肽对增食欲素1和2受体的刺激作用。在大鼠和狗的脑电/肌电(EEG/EMG)实验中，它减少了觉醒，增加了非快速眼动(Non-REM)和REM睡眠，同时保持了自然睡眠结构。ACT-462206在大鼠身上显示出类似焦虑的特性，而不会影响认知和运动功能。因此，它是治疗失眠的潜在候选药物。
The orexin system consists of two G-protein-coupled receptors, the orexin1 and orexin2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexinA and orexinB, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.