7β-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues
7β-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues
复制标题
7 β-甲基取代基是与萘酮类似物活性悬崖相关的结构位点
DOI：
10.1016/j.bmc.2018.07.020
复制
发表时间：
2018-08-07
影响因子：
3.5
通讯作者：
Shao，Li-ming
中科院分区：
文献类型：
--
作者：
Sun，Hui-jiao;Wang，Yu-hua;Shao，Li-ming
With the purpose of identifying novel selectiveκopioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting fromN-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7β-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7β-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7β-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7β-methyl orvinol analogues. Surprisingly, SLL-603, a 7β-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7β-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations.
