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

作     者：Jing Li Tao Zhang Jialin Sun Fengxia Ren Hongxin Jia Zixing Yu Jingchao Cheng Weiguo Shi Jing Li;Tao Zhang;Jialin Sun;Fengxia Ren;Hongxin Jia;Zixing Yu;Jingchao Cheng;Weiguo Shi

作者机构：State Key Laboratory of Toxicology and Medical CountermeasuresBeijing Institute of Pharmacology and ToxicologyBeijing 100850China School of Chemical Engineering and TechnologyTianjin UniversityTianjin 300350China 

出 版 物：《Chinese Chemical Letters》 (中国化学快报（英文版）)

年 卷 期：2022年第33卷第8期

页      面：4107-4110页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 0703[理学-化学] 10[医学] 

主　　题：Peptide-small molecule conjugates Dual MOR/DOR agonists Lead compound Analgesics Physical dependence 

摘      要：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 atμ/δopioid 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.