2. Academic Validation
  3. SLL-023ACP, a KOR/MOR dual agonist, produces potent antinociception with fewer side effects

SLL-023ACP, a KOR/MOR dual agonist, produces potent antinociception with fewer side effects

  • Biochem Biophys Res Commun. 2026 Mar 26:806:153411. doi: 10.1016/j.bbrc.2026.153411.
Yi-Quan Shen 1,  Pan-Wen Liu 2,  Deng-Gao Zhang 3,  Min Liu 4,  Jia-Wen Luo 5,  Yu-Liang Lin 3,  Jiang-Wen Gui 5,  Li-Jin Feng 4,  Jing-Gen Liu 6,  Wei Li 7,  Yu-Jun Wang 8
Affiliations

Affiliations

  • 1 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; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 2 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 3 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China.
  • 4 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 5 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 6 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; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: [email protected].
  • 7 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: [email protected].
  • 8 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China. Electronic address: [email protected].
PMID: 41653647 DOI: 10.1016/j.bbrc.2026.153411
Abstract

Opioids have served as the first-line treatment for pain management. However, their side effects such as addiction potential and constipation have limited their clinical use. Here, we characterized a novel 4,5-epoxymorphinan-based derivative SLL-023ACP, which we previously identified as a high affinity ligand towards κ-opioid receptor (KOR) and μ-opioid receptor (MOR). SLL-023ACP was identified as a full KOR agonist (EC50 = 12.84 nM, Emax = 85.69%) and MOR partial agonist (EC50 = 31.21 nM, Emax = 54.49%) in vitro functional cAMP inhibition assay. In vivo, SLL-023ACP displayed potent antinociceptive effects with ED50 values of 2.6 mg/kg in the hot plate test and 0.15 mg/kg in the abdominal constriction test, exhibiting greater potency than KOR agonist U50,488H and MOR agonist Morphine. Its antinociceptive action is effectively reversed by the non-selective opioid antagonist naloxone and the MOR antagonist CTAP in the hot plate test, and by the KOR antagonist nor-BNI in the abdominal constriction test, indicating its analgesic effects was via MOR and KOR. Importantly, at analgesic doses (2.6 and 5 mg/kg), SLL-023ACP induced no conditioned place preference (CPP) and caused less constipation than morphine, although it did produce significant sedation. Taken together, these results suggest that SLL-023ACP is a potent dual KOR/MOR agonist with a favorable profile of potent analgesia with reduced addiction liability and gastrointestinal dysfunction.

Keywords

Antinociception; Conditioned place preference; Constipation; Dual KOR/MOR agonist; Sedation.

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