Discovery of a highly selective and potent kappa opioid receptor agonist from N-cyclopropylmethyl-7α-piperazinyl -6,14-endoethano-tetrahydronorthebaines

  • Eur J Med Chem. 2026 Oct 5:315:118964. doi: 10.1016/j.ejmech.2026.118964.
Shaoliang Duan  1 ,  Shuyang Hu  2 ,  Yun Fang  1 ,  Min Liu  3 ,  Yuliang Lin  1 ,  Jiangwen Gui  3 ,  Siyuan Tang  1 ,  Chao Zhang  4 ,  Denggao Zhang  1 ,  Xiaobo Mai  1 ,  Songyu Yao  3 ,  Jinggen Liu  5 ,  Liming Shao  6 ,  Wei Fu  1 ,  Yujun Wang  7 ,  Wei Li  8
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China.
  • 2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 4. Jiangxi University of Chinese Medicine, No. 1688 Meiling Road, Nanchang, Jiangxi, 330004, China.
  • 5. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China. Electronic address: [email protected].
  • 6. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: [email protected].
  • 7. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; Jiangxi University of Chinese Medicine, No. 1688 Meiling Road, Nanchang, Jiangxi, 330004, China. Electronic address: [email protected].
  • 8. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 42155170 DOI: 10.1016/j.ejmech.2026.118964
Abstract

Kappa Opioid Receptor (KOR) agonists remain promising candidates for the development of antinociceptive and antipruritic therapeutics. Here, we report the design, synthesis, and biological evaluation of a series of N-cyclopropylmethyl-7α-piperazinyl-6,14-endoethano-tetrahydronorthebaines derived from the 4,5-epoxymorphinan scaffold. Several derivatives displayed subnanomolar to low-nanomolar KOR affinity together with pronounced subtype selectivity in radioligand binding assays. Among them, compound 10e exhibited exceptionally high KOR affinity (Ki = 1.6 pM) and more than 100-fold selectivity over μ- and δ-opioid receptors. In cAMP-based functional assays, compounds 7, 8b, and 10e behaved as KOR agonists, with compound 10e displaying the highest potency (EC50 = 1.41 nM). However, in Tango assays, compound 10e displayed a higher EC50 value of 4912 nM, suggesting G-protein biased signaling. In vivo,10e produced dose-dependent antinociceptive activity in the acetic-acid writhing assay and robust antipruritic effects, while showing no effect in the hot-plate test at doses up to 40 mg/kg. These findings demonstrate that incorporating a 7α-piperazinyl substituent into the 4,5-epoxymorphinan framework yields a highly potent and KOR-selective agonist, and highlight the critical role of the terminal phenylacetamido group in modulating receptor affinity and subtype selectivity.

Keywords
4,5-Epoxymorphinan derivatives; Antinociception; Antipruritic; Kappa opioid receptor; Opioid agonists; Structure-activity relationship.
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