Han Shuang, Zhang Fei-Fei, Xie Xin, Chen Jian-Zhong
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Eur J Med Chem. 2014 Mar 3;74:73-84. doi: 10.1016/j.ejmech.2013.12.018. Epub 2013 Dec 31.
Cannabinoids are potentially useful for the treatment of several diseases. In the present work, we report the syntheses and biological evaluations of 1,2,4-triazolone derivatives designed using a combined approach of scaffold hopping and pharmacophore-oriented method. These compounds exhibited interesting antagonistic activity to the cannabinoid CB1 receptor. The preliminary structure-activity relationships were further discussed. In addition, docking simulations were performed on the good bioactive compound 5c and the low potent compound 5d, respectively, on the basis of homology models of the CB1 and CB2 receptors, which were constructed based on human β2-adrenoreceptor and optimized in a membrane environment by MD simulations. Calculation of the binding modes gave us insights into the structural requirements for improving the cannabinoid receptor bioactivity and selectivity.
大麻素在治疗多种疾病方面具有潜在用途。在本研究中，我们报告了采用骨架跃迁和药效团导向相结合的方法设计的1,2,4-三唑啉酮衍生物的合成及生物学评价。这些化合物对大麻素CB1受体表现出有趣的拮抗活性。进一步讨论了初步的构效关系。此外，分别基于CB1和CB2受体的同源模型对具有良好生物活性的化合物5c和低活性化合物5d进行了对接模拟，这些同源模型是基于人β2-肾上腺素能受体构建的，并通过分子动力学模拟在膜环境中进行了优化。结合模式的计算使我们深入了解了提高大麻素受体生物活性和选择性的结构要求。
