Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
Departamento de Farmacología y Nutrición - Unidad Asociada al IQM (CSIC), Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. Atenas s/n, 28922 Alcorcón, Spain.
Eur J Med Chem. 2014 Feb 12;73:56-72. doi: 10.1016/j.ejmech.2013.11.026. Epub 2013 Dec 7.
Designing drugs with a specific multi-target profile is a promising approach against multifactorial illnesses as Alzheimer's disease. In this work, new indazole ethers that possess dual activity as both cannabinoid agonists CB2 and inhibitors of BuChE have been designed by computational methods. On the basis of this knowledge, the synthesis, pharmacological evaluation and docking studies of a new class of indazoles has been performed. Pharmacological evaluation includes radioligand binding assays with [(3)H]-CP55940 for CB1R and CB2R and functional activity for cannabinoid receptors on isolated tissue. Additionally, in vitro inhibitory assays of AChE/BuChE and the corresponding competition studies have been carried out. The results of pharmacological tests have revealed that three of these derivatives behave as CB2 cannabinoid agonists and simultaneously show BuChE inhibition. In particular, compounds 3 and 24 have emerged as promising candidates as novel cannabinoids that inhibit BuChE by a non-competitive or mixed mechanism, respectively. On the other hand, both molecules show antioxidant properties.
设计具有特定多靶点特征的药物是治疗阿尔茨海默病等多因素疾病的一种有前途的方法。在这项工作中，通过计算方法设计了具有双重活性的新型吲唑醚，作为大麻素激动剂 CB2 和丁酰胆碱酯酶抑制剂。在此基础上，对一类新的吲唑类化合物进行了合成、药理评价和对接研究。药理评价包括用 [(3)H]-CP55940 进行 CB1R 和 CB2R 的放射性配体结合测定以及对分离组织上的大麻素受体的功能活性。此外，还进行了 AChE/BuChE 的体外抑制测定和相应的竞争研究。药理试验的结果表明，其中三个衍生物表现为 CB2 大麻素激动剂，同时表现出丁酰胆碱酯酶抑制作用。特别是，化合物 3 和 24 分别以非竞争性或混合机制抑制 BuChE，作为新型大麻素具有很大的潜力。另一方面，这两种分子都具有抗氧化特性。
