International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology.

IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmacological Reviews Pub Date : 2024-08-15 DOI:10.1124/pharmrev.123.000953
Jyrki P Kukkonen, Laura H Jacobson, Daniel Hoyer, Maiju K Rinne, Stephanie L Borgland
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Abstract

The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX1 and OX2 Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia. In addition to sleep and wakefulness, the orexin system appears to be a central player at least in addiction and reward, and has a role in depression, anxiety and pain gating. Additional antagonists and agonists are in development to treat, for instance, insomnia, narcolepsy with or without cataplexy and other disorders with excessive daytime sleepiness, depression with insomnia, anxiety, schizophrenia, as well as eating and substance use disorders. The orexin system has thus proved an important regulator of numerous neural functions and a valuable drug target. Orexin prepro-peptide and orexin receptors are also expressed outside the central nervous system, but their potential physiological roles there remain unknown. SIGNIFICANCE STATEMENT: The orexin system was discovered 25 years ago and immediately emerged as an essential sleep-wakefulness regulator. This discovery has tremendously increased the understanding of these processes and has thus far resulted in the market approval of three orexin receptor antagonists, which promote more physiological aspects of sleep than previous hypnotics. Further, orexin receptor agonists and antagonists with different pharmacodynamic properties are in development since research has revealed additional potential therapeutic indications. Orexin receptor signaling is complex and may represent novel features.

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国际基础和临床药理学联盟第 CXIV 期:俄瑞欣受体的功能、命名和药理学。
奥曲肽系统由多肽递质奥曲肽-A 和-B 以及与 G 蛋白偶联的奥曲肽受体 OX1 和 OX2 组成。奥曲肽受体能够与所有四种异三聚体 G 蛋白家族偶联,奥曲肽受体的信号传导还具有其他复杂的特征。该系统于 25 年前被发现,并立即被确定为睡眠和觉醒的中枢调节器;嗜睡症伴惊厥的症状就是一个例证,在这种疾病中,奥曲肽能神经元会退化。这些发现随后被转化为药物的发现和开发,迄今已有三种治疗失眠的奥曲肽受体拮抗剂在临床上使用。除了睡眠和觉醒之外,奥曲肽系统似乎至少在成瘾和奖赏方面发挥着核心作用,并在抑郁、焦虑和疼痛门控方面发挥作用。目前正在开发更多的拮抗剂和激动剂,用于治疗失眠、伴有或不伴有惊厥的嗜睡症和其他白天过度嗜睡的疾病、伴有失眠的抑郁症、焦虑症、精神分裂症以及饮食和药物使用障碍等。因此,奥曲肽系统已被证明是众多神经功能的重要调节器和有价值的药物靶点。奥曲肽前体和奥曲肽受体在中枢神经系统之外也有表达,但它们在中枢神经系统中的潜在生理作用尚不清楚。意义声明 25 年前,人们发现了奥曲肽系统,并立即将其视为睡眠-觉醒的重要调节器。这一发现极大地提高了人们对这些过程的认识,迄今已有三种奥曲肽受体拮抗剂获得市场批准,它们比以往的催眠药更能促进生理性睡眠。此外,具有不同药效学特性的奥曲肽受体激动剂和拮抗剂也在开发中,因为研究发现了更多潜在的治疗适应症。奥曲肽受体信号传导非常复杂,可能具有新的特征。
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来源期刊
Pharmacological Reviews
Pharmacological Reviews 医学-药学
CiteScore
34.70
自引率
0.50%
发文量
40
期刊介绍: Pharmacological Reviews is a highly popular and well-received journal that has a long and rich history of success. It was first published in 1949 and is currently published bimonthly online by the American Society for Pharmacology and Experimental Therapeutics. The journal is indexed or abstracted by various databases, including Biological Abstracts, BIOSIS Previews Database, Biosciences Information Service, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Index Medicus, Index to Scientific Reviews, Medical Documentation Service, Reference Update, Research Alerts, Science Citation Index, and SciSearch. Pharmacological Reviews offers comprehensive reviews of new pharmacological fields and is able to stay up-to-date with published content. Overall, it is highly regarded by scholars.
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