The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist.
The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist.
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DOI：
10.1038/tp.2014.30
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发表时间：
2014-07-15
影响因子：
6.8
通讯作者：
Sames D
中科院分区：
文献类型：
--
作者：
Gassaway MM;Rives ML;Kruegel AC;Javitch JA;Sames D
目前抑郁症和相关病症的药物治疗存在主要问题，例如反应率低、治疗效果起效慢、随着时间的推移失去功效和严重的副作用。因此，迫切需要探索解决这些问题的新的治疗方法。有趣的是，非典型抗抑郁药噻奈普汀已经部分达到了这些临床目标。然而，尽管有三十年的基础和临床研究，噻奈普汀的分子靶点，以及其作用机制，仍然难以捉摸。在此，我们报告了噻奈普汀作为μ-阿片受体（莫尔）激动剂的特性。使用放射性配体结合和基于细胞的功能测定，包括基于生物发光共振能量转移的G蛋白活化和cAMP蓄积测定，我们将噻奈普汀鉴定为有效的莫尔激动剂（Ki人为383±183 nM，EC 50人为194±70 nM，EC 50小鼠为641±120 nM，用于G蛋白活化）。噻奈普汀也是一种完全的δ-阿片受体（DOR）激动剂，尽管效力要低得多（对于G蛋白活化，人的EC 50为37.4±11.2 μM，小鼠的EC 50为14.5±6.6 μM）。相反，噻奈普汀对κ-阿片受体（KOR，人和大鼠）无活性。基于这些药理学数据，我们认为莫尔的激活（或莫尔和DOR的双重激活）可能是引发该药物许多已知急性和慢性效应（包括其抗抑郁和抗焦虑作用）的初始分子事件。
Current pharmacological treatments of depression and related disorders suffer from major problems, such as a low rate of response, slow onset of therapeutic effects, loss of efficacy over time and serious side effects. Therefore, there is an urgent need to explore new therapeutic approaches that address these issues. Interestingly, the atypical antidepressant tianeptine already meets in part these clinical goals. However, in spite of three decades of basic and clinical investigations, the molecular target of tianeptine, as well as its mechanism of action, remains elusive. Herein, we report the characterization of tianeptine as a μ-opioid receptor (MOR) agonist. Using radioligand binding and cell-based functional assays, including bioluminescence resonance energy transfer-based assays for G-protein activation and cAMP accumulation, we identified tianeptine as an efficacious MOR agonist (Ki Human of 383±183 nM and EC50 Human of 194±70 nM and EC50 Mouse of 641±120 nM for G-protein activation). Tianeptine was also a full δ-opioid receptor (DOR) agonist, although with much lower potency (EC50 Human of 37.4±11.2 μM and EC50 Mouse of 14.5±6.6 μM for G-protein activation). In contrast, tianeptine was inactive at the κ-opioid receptor (KOR, both human and rat). On the basis of these pharmacological data, we propose that activation of MOR (or dual activation of MOR and DOR) could be the initial molecular event responsible for triggering many of the known acute and chronic effects of this agent, including its antidepressant and anxiolytic actions.
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影响因子：
11
作者：
通讯作者：
--
DOI：
10.1007/bf03190130
发表时间：
1990-01-01
影响因子：
1.9
作者：
COUET, W;GIRAULT, J;FOURTILLAN, JB
通讯作者：
FOURTILLAN, JB
影响因子：
3.4
作者：
Kole, MHP;Swan, L;Fuchs, E
通讯作者：
Fuchs, E
影响因子：
4.8
作者：
Vezzi, Vanessa;Onaran, H. Ongun;Costa, Tommaso
通讯作者：
Costa, Tommaso
影响因子：
7.3
作者：
SCHILLER, PW;WELTROWSKA, G;LEMIEUX, C
通讯作者：
LEMIEUX, C