European journal of medicinal chemistry · 2025
D-morphinan analogs with favorable pharmacokinetic profiles as dual-acting antidepressants.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Ji Jing, Hu Zhengtao, Zheng Fuqiang, Zheng Jiefang, Cheng Jiaxin, Zayniddin Nuriddinov, Abduahadi Safomuddin, Wang Guan, Gong Xudong, Pan Libiao, Li Pengcheng, Zhao Jiangyu, Hu Tianwen, Zhu Weiliang, Shen Jingshan, Tian Guanghui, Aisa Haji Akber, He Yang
Аннотация
Dextromethorphan (DM) is a dual inhibitor of NMDAR and SERT (IC50 (NMDAR): IC50 (SERT) = 31), but lacks therapeutic clinical value for the treatment of depression due to its low exposure in the human body. In this study, a series of d-morphinan derivatives were designed, synthesized and evaluated both in vitro and in vivo to identify dual inhibitors with improved metabolic stability. Structure-activity relationship studies revealed that a methyl group at the morphinan N-17 position is essential for maintaining SERT activity. Amino-morphinan compounds 24 and 27 exhibited moderate yet more balanced inhibitory activity against both NMDAR and SERT (1< IC50(NMDAR): IC50(SERT) < 5). Compared to DM, compound 24 demonstrated favorable metabolic stability and higher plasma exposure. In vivo, 24 showed significant antidepressant-like effects in the forced swim test in mice after acute administration.