Citation: Jing Li, Tao Zhang, Jialin Sun, Fengxia Ren, Hongxin Jia, Zixing Yu, Jingchao Cheng, Weiguo Shi. Synthesis and evaluation of peptide–fentanyl analogue conjugates as dual µ/δ-opioid receptor agonists for the treatment of pain[J]. Chinese Chemical Letters, ;2022, 33(8): 4107-4110. doi: 10.1016/j.cclet.2021.11.036 shu

Synthesis and evaluation of peptide–fentanyl analogue conjugates as dual µ/δ-opioid receptor agonists for the treatment of pain

Jing Li ^{a, b} ,
Tao Zhang ^a ,
Jialin Sun ^a ,
Fengxia Ren ^a ,
Hongxin Jia ^a ,
Zixing Yu ^a ,
Jingchao Cheng ^a ,
Weiguo Shi ^{a, *,}

a.
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
b.
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China

shiwg1988@126.com

Received Date: 24 September 2021
Revised Date: 24 October 2021
Accepted Date: 10 November 2021
Available Online: 17 November 2021

Figures(4)

Novel peptide-fentanyl analogue conjugates were synthesized by the covalent coupling of carfentanyl derivatives to the C-terminus or N-terminus of the conformationally constrained dermorphin tetrapeptide BVD03 via a chemical linker. The carfentanyl-related analogues displayed distinct binding and functional activities at µ/δ opioid receptors (MOR/DOR) and antinociceptive effects when conjugated to the peptide. The most potent compound, SW-LJ-11, displayed mixed MOR/DOR agonist properties in the low nanomolar range and significant analgesic efficacy in vivo in four classic mouse models of pain. Interestingly, SW-LJ-11 did not exhibit any physical dependence or respiratory depression, in contrast to an equipotent analgesic dose of morphine or BVD03, indicating that the use of opioid peptide–fentanyl analogue conjugates as dual MOR/DOR agonists may be a promising strategy for obtaining safer opioids.
- Peptide-small molecule conjugates,
- Dual MOR/DOR agonists,
- Lead compound,
- Analgesics,
- Physical dependence
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沈阳化工大学材料科学与工程学院沈阳 110142