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Li, Zixiang; Ye, Rufeng; He, Qian; Lu, Jiashuo; Sun, Yanting; Sun, Xiujian; Tang, Siyuan; Hu, Shuyang; Chai, Jingrui; Kong, Linghui; Liu, Xiaoning; Chen, Jing; Fang, Yun; Lan, Yingjie; Xie, Qiong; Liu, Jinggen; Shao, Liming; Fu, Wei; Wang, Yujun; Li, Wei
Journal of medicinal chemistry, 05/2024, Volume: 67, Issue: 9Journal Article
Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, K i = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; 35SGTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20–0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20–0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.
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