Design and synthesis of a novel series of N-alkyl isatin acylhydrazone derivatives that act as selective cannabinoid receptor 2 agonists for the treatment of neuropathic pain
Design and synthesis of a novel series of N-alkyl isatin acylhydrazone derivatives that act as selective cannabinoid receptor 2 agonists for the treatment of neuropathic pain
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DOI：
10.1021/jm8002203
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发表时间：
2008-08-28
影响因子：
7.3
通讯作者：
Naguib, Mohamed
中科院分区：
文献类型：
--
作者：
Diaz, Philippe;Xu, Jijun;Naguib, Mohamed
使用大麻素受体2（CB 2）激动剂治疗神经性疼痛的兴趣日益增长。我们已经合成了一系列新的N-烷基靛红酰腙衍生物，并已确定和表征了其中几个作为新的类似物具有高功能活性和选择性，在人CB 2受体使用[S-35] GTP-γ-S测定。测定化合物28、33、40、48和58对人CB 2和CB 1的结合亲和力。这一新系列的结构-活性关系研究导致了我们的先导化合物化合物33（MDA 19）的优化。化合物33在神经性疼痛的大鼠模型中具有有效的抗异常性疼痛作用，但不影响大鼠运动活性。还发现了更有效和更CB 2受体选择性的化合物，包括化合物37、40和48。
There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain. We have synthesized a novel series of N-alkyl isatin acylhydrazone derivatives and have identified and characterized several of them as novel analogues with high functional activity and selectivity at human CB2 receptors using [S-35]GTP-gamma-S assays. Binding affinities at human CB2 and CB1 were determined for Compounds 28, 33, 40, 48, and 58. Structure-activity relationship studies of this novel series led to optimization of our lead compound, Compound 33 (MDA19). Compound 33 possessed potent antiallodynic effects in a rat model of neuropathic pain but did not affect rat locomotor activity. More potent and more CB2-receptor-selective compounds, including compounds 37, 40, and 48, were also discovered.