Shi Ying, Duan Yan-Hui, Ji Yue-Yang, Wang Zhi-Long, Wu Yan-Ran, Gunosewoyo Hendra, Xie Xiao-Yu, Chen Jian-Zhong, Yang Fan, Li Jing, Tang Jie, Xie Xin, Yu Li-Fang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, China.
Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Bio-Medicine, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University , 1239 Siping Road, Shanghai 200092, China.
J Med Chem. 2017 Aug 24;60(16):7067-7083. doi: 10.1021/acs.jmedchem.7b00724. Epub 2017 Aug 3.
Selective CB agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB antagonists (27 or 28, IC = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB over CB receptor. Particularly, compound 57 displayed a potent agonist activity on the CB receptor (EC = 114-142 nM) without observable agonist or antagonist activity on the CB receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.
选择性CB激动剂代表了一种有吸引力的治疗策略，用于治疗各种疾病，而不会产生由CB受体介导的精神副作用。我们对一种黑市设计药物SDB-001进行了合理优化，从而鉴定出强效且选择性的CB激动剂。在3-氨基烷基吲哚上进行7-甲氧基或7-甲硫基取代会产生强效CB拮抗剂（27或28，IC = 16 - 28 nM）。将吲哚环3位上的氨基烷基替换到2位上，显著提高了对CB受体而非CB受体的激动剂选择性。特别地，化合物57对CB受体表现出强效激动剂活性（EC = 114 - 142 nM），而对CB受体没有可观察到的激动剂或拮抗剂活性。此外，在多发性硬化症的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中，57显著减轻了临床症状并保护小鼠中枢神经系统免受免疫损伤。
