Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, Maryland, United States.
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Camerino, Italy.
Med Res Rev. 2023 Sep;43(5):1607-1667. doi: 10.1002/med.21959. Epub 2023 Apr 10.
Orexin-A and orexin-B, also named hypocretin-1 and hypocretin-2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein-coupled receptors, namely orexin receptor type 1 (OX1-R) and type 2 (OX2-R), which share 64% amino acid identity. Given the wide expression of OX-Rs in different central nervous system and peripheral areas and the several pathophysiological functions in which they are involved, including sleep-wake cycle regulation (mainly mediated by OX2-R), emotion, panic-like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1-R), both subtypes represent targets of interest for many structure-activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual-orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1-R and OX2-R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype-selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1-R/OX2-R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX-R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly-pharmacology applications and multitarget ligands have also been considered.
食欲素 A 和食欲素 B，也称为下丘脑泌素 1 和下丘脑泌素 2，是两种在哺乳动物物种中高度保守的下丘脑神经肽。它们的作用是由两种不同的 G 蛋白偶联受体介导的，即食欲素受体 1（OX1-R）和 2（OX2-R），它们具有 64%的氨基酸同一性。鉴于 OX-Rs 在不同的中枢神经系统和外周区域广泛表达，以及它们参与的几种病理生理功能，包括睡眠-觉醒周期调节（主要由 OX2-R 介导）、情绪、恐慌样行为、焦虑/应激、食物摄入和能量稳态（主要由 OX1-R 介导），这两种亚型都是许多制药公司和学院进行的结构-活性关系（SAR）研究的目标。然而，在 2017 年之前，研究主要集中在双食欲素配体上，而且研究的化学型有限。分析特性，包括与激动剂和拮抗剂结合的 OX1-R 和 OX2-R 的解析结构，提高了对受体识别的分子基础的理解，并且是药物化学家设计亚型选择性配体的资产。本综述重点介绍了作为双或亚型选择性 OX1-R/OX2-R 激动剂和拮抗剂的小分子的药物化学方面，属于不同的化学型，并在过去几年中得到了发展，包括用于分子成像的放射性标记的 OX-R 配体。此外，还讨论了在不同神经精神疾病中研究最多的配体的药理学作用，如睡眠、情绪、物质使用和饮食障碍，以及疼痛。多药理学应用和多靶标配体也已被考虑。
