Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14- endo ethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

  • J Med Chem. 2024 May 9;67(9):7112-7129. doi: 10.1021/acs.jmedchem.3c02439.
Zixiang Li  1 ,  Rufeng Ye  2  3 ,  Qian He  1 ,  Jiashuo Lu  2  4 ,  Yanting Sun  5 ,  Xiujian Sun  5 ,  Siyuan Tang  1 ,  Shuyang Hu  2 ,  Jingrui Chai  2 ,  Linghui Kong  1 ,  Xiaoning Liu  6 ,  Jing Chen  2 ,  Yun Fang  1 ,  Yingjie Lan  1 ,  Qiong Xie  1 ,  Jinggen Liu  2  3  5 ,  Liming Shao  1 ,  Wei Fu  1 ,  Yujun Wang  2  3  6 ,  Wei Li  1
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China.
  • 2. CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai 201203, China.
  • 3. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 4. Department of Pharmacy, Dalian Medical University, Dalian 116044, China.
  • 5. Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurobiology of Zhejiang Province, Hangzhou 310053, China.
  • 6. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, Shandong, China.
PMID: 38647397 DOI: 10.1021/acs.jmedchem.3c02439
Abstract

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, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS 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.

Products