Pharmacological Characterization of SLL-022CCP, a Selective κ‑Opioid Receptor Agonist with Potent Antinociceptive Effects and Low Central Side Effects

  • ACS Omega. 2026 Jun 4;11(24):36322-36336. doi: 10.1021/acsomega.6c04362.
Jiang-Wen Gui  1  2  3 ,  Jia-Wen Luo  1  2  3 ,  Deng-Gao Zhang  4 ,  Zhi-Wen Wang  2  5 ,  Chao Zhang  2  5 ,  Meng Sun  2  6 ,  Jia-Qi Tan  2  7 ,  Si-Yuan Tang  4 ,  Shao-Liang Duan  4 ,  Yu-Liang Lin  4 ,  Min Liu  2 ,  Li-Jin Feng  2 ,  Li-Ming Shao  4 ,  Jing-Gen Liu  2  8 ,  Pan-Wen Liu  2 ,  Wei Li  4 ,  Yu-Jun Wang  2  3
Affiliations
  • 1. School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China.
  • 2. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • 3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai 201203, China.
  • 4. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China.
  • 5. Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, China.
  • 6. Yantai University, Yantai, Shandong 264117, China.
  • 7. Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, Liaoning 110016, China.
  • 8. Department of Neurobiology and Acupuncture Research, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No.548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China.
PMID: 42368158 DOI: 10.1021/acsomega.6c04362
Abstract

The κ-opioid receptor (KOR) is recognized as a promising therapeutic target for the development of nonaddictive analgesics. However, the clinical utility of typical KOR agonists is limited by central adverse effects. SLL-022CCP is a novel KOR-selective ligand derived from a northebaine-based 4,5-epoxymorphinan scaffold, and we have previously demonstrated its high binding affinity for KOR. In this study, we performed a systematic evaluation of SLL-022CCP through in vitro and in vivo assays. In vitro, SLL-022CCP acted as an extremely potent full agonist at the KOR, inhibiting cAMP production with an EC50 of 0.002 nM, and exhibited high receptor subtype selectivity over the μ-opioid receptor (MOR, EC50 = 1.6 nM) and δ-opioid receptor (DOR, EC50 = 30.0 nM). SLL-022CCP recruited β-arrestin at the KOR with an EC50 of 15.5 nM and at the MOR with an EC50 of 668.0 nM. Molecular docking data for SLL-022CCP revealed that it maintains canonical interactions with the KOR orthosteric site while extending its terminal phenyl moiety into a hydrophobic subpocket. In vivo, SLL-022CCP produced potent antinociception in the hot plate test (ED50 = 1.816 mg/kg), acetic acid-induced writhing test (ED50 = 0.113 mg/kg), and significant antipruritic effects in the histamine-induced itch test (ED50 = 0.079 mg/kg) and CFA-induced itch test (ED50 = 0.105 mg/kg). The antinociceptive effects of SLL-022CCP were antagonized by the KOR-selective antagonist Nor-BNI, but not by the MOR antagonist CTAP (1 mg/kg, i.p.), supporting primarily KOR-mediated activity. Importantly, at the antinociceptive dose, SLL-022CCP did not elicit significant motor incoordination or conditioned place aversion (CPA) under current experimental conditions, while eliciting transient sedation, distinguishing it from the typical arylacetamide derivatives, like U50,488H. Collectively, these results identify SLL-022CCP as a highly potent and selective KOR agonist with a unique pharmacological profile that exhibits robust antinociceptive and antipruritic effects with low central side effects.

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