Zhang Li-Ming, Zhao Nan, Guo Wen-Zhi, Jin Zeng-Liang, Qiu Zhi-Kun, Chen Hong-Xia, Xue Rui, Zhang You-Zhi, Yang Ri-Fang, Li Yun-Feng
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, PR China.
Department of Anesthesiology, General Hospital of Beijing Military Command, Beijing 100007, China.
Neuropharmacology. 2014 Jun;81:116-25. doi: 10.1016/j.neuropharm.2013.09.016. Epub 2013 Sep 22.
It has been demonstrated that the translocator protein (18 kDa) (TSPO) plays an important role in stress-response and stress-related disorders, such as anxiety and depression, by affecting the production of neurosteroids, supporting the potential use of selective TSPO ligands as antidepressant or anxiolytic drugs. N-ethyl-N-(2-pyridinylmethyl)- 2-(3,4-ichlorophenyl)- 7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride (YL-IPA08), a novel TSPO ligand that has been synthesized at our institute, exerted a high affinity for TSPO in a crude mitochondrial fraction prepared from rat cerebellum but exhibited only a negligible affinity for the central benzodiazepine receptor. As expected, YL-IPA08 incubation with the cultured rat astrocyte cells increased the pregnenolone and progesterone concentration from the cultured medium. Moreover, YL-IPA08 produced significant antidepressant-like and anxiolytic-like effects in a series of mouse and rat behavior models. In addition, the antidepressant-like behavior of YL-IPA08 was totally blocked by the TSPO antagonist PK11195 in a tail suspension test, and the anxiolytic effect was blocked by PK11195 but not by a CBR antagonist in the elevated plus-maze test. Furthermore, compared with the CBR agonist diazepam, YL-IPA08 had no myorelaxant effects and did not affect the motor coordination, memory or hexobarbitone-induced sleep in mice. Overall, these results indicate that YL-IPA08 is a more potent and selective TSPO ligand, which exerts antidepressant-like and anxiolytic-like effects on behaviors that are mediated by TSPO but does not cause the side effects that are typically associated with conventional benzodiazepines.
已证实，转位蛋白（18 kDa）（TSPO）通过影响神经甾体的产生，在应激反应及与应激相关的疾病（如焦虑和抑郁）中发挥重要作用，这支持了将选择性TSPO配体用作抗抑郁或抗焦虑药物的可能性。N-乙基-N-（2-吡啶甲基）-2-（3,4-二氯苯基）-7-甲基咪唑并[1,2-a]吡啶-3-乙酰胺盐酸盐（YL-IPA08）是我们研究所合成的一种新型TSPO配体，对从大鼠小脑制备的粗线粒体部分中的TSPO具有高亲和力，但对中枢苯二氮䓬受体的亲和力可忽略不计。正如预期的那样，将YL-IPA08与培养的大鼠星形胶质细胞一起孵育可提高培养基中孕烯醇酮和孕酮的浓度。此外，YL-IPA08在一系列小鼠和大鼠行为模型中产生了显著的抗抑郁样和抗焦虑样作用。另外，在悬尾试验中，YL-IPA08的抗抑郁样行为被TSPO拮抗剂PK11195完全阻断，在高架十字迷宫试验中，其抗焦虑作用被PK11195阻断，但未被CBR拮抗剂阻断。此外，与CBR激动剂地西泮相比，YL-IPA08没有肌松作用，也不影响小鼠的运动协调、记忆或己巴比妥诱导的睡眠。总体而言，这些结果表明，YL-IPA08是一种更有效且更具选择性的TSPO配体，它对由TSPO介导的行为产生抗抑郁样和抗焦虑样作用，但不会引起通常与传统苯二氮䓬类药物相关的副作用。
