6-Methoxy-N-alkyl Isatin Acylhydrazone Derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Inverse Agonists: Design, Synthesis, and Binding Mode Prediction
6-Methoxy-N-alkyl Isatin Acylhydrazone Derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Inverse Agonists: Design, Synthesis, and Binding Mode Prediction
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DOI：
10.1021/jm801353p
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发表时间：
2009-01-22
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;Phatak, Sharangdhar S.;Naguib, Mohamed
最近，我们发现并报道了一系列N-烷基靛红酰腙衍生物，它们是有效的CB 2激动剂。在这里，我们描述了一系列新的选择性CB 2反向激动剂，从引入甲氧基部分的位置6的靛红支架。这些新的6-甲氧基-N-烷基靛红酰腙衍生物对人CB 2具有高的功能活性和选择性。化合物16（MDA 77）对CB 2具有高活性（EC 50 = 5.82 nM），对CB 1没有活性。化合物15（MDA 55）（Ki = 89.9nM，EC 50 = 88.2nM，在CB 2处）在神经性疼痛的动物模型中抑制化合物1（MDA 7）（一种选择性CB 2激动剂）的作用。本文提出的分子模拟研究代表了基于β（2）-肾上腺素能受体结构的CB 2的首次研究。基于配体的同源性模型的CB 2结合位点的开发，并在我们的研究结果的基础上，我们提出了这类反向激动剂与CB 2的一般结合模式。
Recently, we discovered and reported a series of N-alkyl isatin acylhydrazone derivatives that are potent CB2 agonists. Here, we describe a novel series of selective CB2 inverse agonists resulting from introduction of a methoxy moiety in position 6 of the isatin scaffold. These novel 6-methoxy-N-alkyl isatin acylhydrazone derivatives exhibited high CB2 functional activity and selectivity at human CB2. Compound 16 (MDA77) had high activity (EC50 = 5.82 nM) at CB2 and no activity at CB1. Compound 15 (MDA55) (K-i = 89.9 nM, EC50 = 88.2 nM at CB2) inhibited the effect of compound 1 (MDA7), a selective CB2 agonist, in an animal model of neuropathic pain. The molecular modeling study presented here represents a first study of CB2 based on the structure of beta(2)-adrenergic receptor. A ligand-based homology model of the CB2 binding site was developed, and on the basis of our results, we propose a general binding mode for this class of inverse agonists with CB2.