2. Academic Validation
  3. 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

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

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.

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