Synthesis and biological evaluation of beta(2)-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold
Synthesis and biological evaluation of beta(2)-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold
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带有2-氨基-2-苯基乙醇支架的β(2)-肾上腺素受体激动剂的合成和生物学评价
DOI：
10.1016/j.ejmech.2018.04.041
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发表时间：
2018
影响因子：
6.7
通讯作者：
Cheng Maosheng
中科院分区：
文献类型：
--
作者：
Ge Xinyue;Woo Anthony Yiu-Ho;Xing Gang;Mo Yongmei;Zhao Ying;Li Jinyan;Yan Haining;Pan Li;Lin Bin;Cheng Maosheng
合成了一系列以2-氨基-2-苯乙醇为支架的β2-肾上腺素能受体激动剂。细胞实验和体外豚鼠气管松弛实验表明，8-羟基-5-（2-羟基-1-（4-羟基苯基）氨基）乙基)喹啉-2(1H)- 1（化合物5j）具有较好的药理作用。随后发现5j的(S)-异构体是活性对映体，其ec50值为1.26 nM，可刺激β2-肾上腺素受体介导的cAMP积累，并且β2的选择性大大高于β1亚型。β2-肾上腺素受体分子对接揭示的(S)-5j的推测结合模式类似于激动剂结合模式。综上所述，化合物(S)-5是一种值得进一步研究开发β2-肾上腺素能受体激动剂的化合物。
A new series of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold was synthesized. Evaluation of the compounds using cell assays and anin vitroguinea pig trachea relaxation assay showed that 8-hydroxy-5-(2-hydroxy-1-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one (compound5j) has the best pharmacological profile among all the evaluated compounds. The(S)-isomer of5jwas subsequently found to be the active enantiomer with a promising EC50value of 1.26 nM in stimulating β2-adrenoceptor-mediated cAMP accumulation and a substantially higher selectivity for the β2than for the β1subtype. The putative binding mode of(S)-5jrevealed by molecular docking of the β2-adrenoceptor resembles that in agonist binding. Taken together, these results showed that compound(S)-5jis a promising compound worthy of further study for the development of β2-adrenoceptor agonists.