D-161, a novel pyran-based triple monoamine transporter blocker: Behavioral pharmacological evidence for antidepressant-like action
D-161, a novel pyran-based triple monoamine transporter blocker: Behavioral pharmacological evidence for antidepressant-like action
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DOI：
10.1016/j.ejphar.2008.05.008
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发表时间：
2008-07-28
影响因子：
5
通讯作者：
Reith, Maarten E. A.
中科院分区：
文献类型：
--
作者：
Dutta, Aloke K.;Ghosh, Balaram;Reith, Maarten E. A.
在药理学和临床研究中，多巴胺能活性缺乏与抑郁状态有关。目前抑郁症的药物治疗主要涉及调节血清素能和去甲肾上腺素能系统，而不是多巴胺能神经传递。现有的抗抑郁药物治疗有许多缺点，因为相当多的人要么是难治性的，要么对抗抑郁药物产生耐受性，导致复发。此外，目前的治疗方法起效缓慢，往往对有效治疗构成挑战。在我们努力开发影响上述三种单胺系统的新分子的过程中，我们发现了结构独特的吡喃衍生物，具有各种抑制单胺转运体的特征。一个铅分子。D-161具有三单胺转运体抑制活性，对去甲肾上腺素转运体（NET）的亲和性最高，其次是血清素转运体（SERT）和多巴胺转运体（DAT）。D-161在大鼠强迫游泳实验和小鼠悬尾实验中均表现出明显的降低静止不动的活性。此外，运动活动测试结果表明，D-161减少不动性不是由于运动激活，因为在与强迫游泳试验相同的条件下给予相同剂量的药物时，没有观察到明显的运动激活。这些结果表明，新型不对称吡喃衍生物D-161具有独特的分子结构，具有三单胺转运体抑制活性，可能具有有效的抗抑郁活性。(C) 2008 Elsevier B.V.版权所有
Deficiency in dopaminergic activity has been linked to a depressed state in pharmacological and clinical studies. Current pharmacological treatment for depression primarily involves modulation of serotonergic and noradrenergic systems but not dopaminergic neurotransmission. Available pharmacotherapy for depression has a number of drawbacks as a significant number of people are either refractory or develop tolerance to the antidepressant agents resulting in relapse. Furthermore, the slow onset of action Of Current therapies often poses a challenge for effective treatment. In our effort to develop novel molecules impacting all three above mentioned monoamine systems, we discovered structurally unique pyran derivatives with various profiles in inhibiting monoamine transporters. One of our lead molecules. D-161 exhibited triple monoamine transporter inhibitory activity with the highest affinity for norepinephrine transporter (NET) followed by its affinity for serotonin transporter (SERT) and dopamine transporter (DAT). D-161 exhibited potent activity in reducing immobility significantly in the rat forced swim test as well as in the mouse tail suspension test. Moreover, results from locomotor activity tests indicated that the reduction of immobility by D-161 was not due to motor activation as no significant motor activation was observed when the rats were subjected to the same doses of drug under the same conditions as in the forced swim test. These results suggest that the novel asymmetric pyran derivative D-161 with unique molecular structure exhibiting triple monoamine transporter inhibitory activity could possess potent antidepressant activity. (C) 2008 Elsevier B.V. All rights reserved.