Design, Synthesis and Evaluation of the Antidepressant and Anticonvulsant Activities of Triazole-Containing Benzo[d]oxazoles.
Design, Synthesis and Evaluation of the Antidepressant and Anticonvulsant Activities of Triazole-Containing Benzo[d]oxazoles.
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DOI：
10.2174/1871527315666160822112501
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发表时间：
2017-02
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通讯作者：
Ming‐Xia Song;Bao-Qi Rao;Bin-Bin Cheng-Bin;Y. Wu;Hong Zeng;You-Gen Luo;Xianqing Deng
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作者：
Ming‐Xia Song;Bao-Qi Rao;Bin-Bin Cheng-Bin;Y. Wu;Hong Zeng;You-Gen Luo;Xianqing Deng
背景癫痫和抑郁症是严重威胁人类生命健康的两种常见疾病。一个共同的神经生物学基板导致的双向关系和高共病发生的两种疾病。最近，越来越多的癫痫患者（PWE）需要某种形式的抗抑郁药物。然而，由于某些原因，大多数可用的抗抑郁药不足以治疗PWE。因此，寻找具有抗惊厥和抗抑郁活性的新型且日益有效的药物是必要的。方法设计并合成了一系列2-取代-6-（4 H-1，2，4-三唑-4-基）苯并[d]恶唑类化合物（5a-p）。采用小鼠最大电休克（MES）和皮下注射戊四唑（scPTZ）癫痫模型评价其抗惊厥活性。采用强迫游泳试验（FST）筛选其抗抑郁活性。结果所有化合物均表现出不同程度的抗MES活性，其中5g和5 j的ED 50值分别为31.7和12.7mg/kg。此外，5g和5 j还表现出良好的抗scPTZ活性和较低的神经毒性。有趣的是，这些化合物在FST中也显示出良好的抗抑郁活性。悬尾试验和旷场试验也证实了5g的药效。氨基硫脲（γ-氨基丁酸合成酶抑制剂）预处理可显著增加MES中5g的ED_（50），并逆转FST中5g的不动时间的缩短。结论含三唑的苯并[d]恶唑是开发抗惊厥和抗抑郁活性化合物的良好骨架。化合物5g具有显著的抗抑郁和抗惊厥活性，其作用机制与GABA能系统有关。
BACKGROUND Epilepsy and depression are two of the common diseases seriously threatening life and health of human. A shared neurobiological substrate led to the bidirectional relationship and high comorbid occurrence of the two disorders. Recently, an increasing number of patients with epilepsy (PWE) require some form of antidepressant medication. However, most of the available antidepressants are inadequate for PWE for some reasons. So, the search for novel and increasingly effective drugs with anticonvulsant and antidepressant activities is necessary. METHODS A series of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles (5a-p) were designed and synthesized. Their anticonvulsant activities were evaluated using maximal electroshock shock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. Their antidepressant activities were screened with the forced swimming test (FST). RESULTS All the compounds showed anti-MES activities in different degree, among which 5g and 5j were the most promising one with ED50 value of 31.7 and 12.7 mg/kg, respectively. What's more, 5g and 5j also exhibited nice anti-scPTZ activities and low neurotoxicity. Interestingly, these compounds also showed good antidepressant activities in FST. And the efficacy of 5g were also confirmed by a tail suspension test and a open field test. The pretreatment of thiosemicarbazide (an inhibitor of γ- aminobutyric acid synthesis enzyme) significantly increased the ED50 of 5g in MES and reversed the reductions in the immobility time of 5g in FST. CONCLUSION Triazole-containing benzo[d]oxazole is a good skeleton to develop compounds with both anticonvulsant and antidepressant activities. We have got the compound 5g, which display remarkable antidepressant and anticonvulsant activities, and the GABAergic system was involved in the action mechanism of 5g.