• Mengna Zhang, Biao Xu, Ning Li, Hui Liu, Xuerui Shi, Qinqin Zhang, Yanbin Shi, Kangtai Xu, Jian Xiao, Dan Chen, Hanwen Zhu, Yulong Sun, Ting Zhang, Run Zhang, and Quan Fang.
• Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.
• J. Med. Chem. 2020 Dec 24; 63 (24): 15709-15725.

AbstractIn a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized. The cyclized analogs and their linear counterparts behaved as multifunctional agonists at both opioid and NPFF receptors in vitro and produced potent analgesia without tolerance development. In comparison to 0, cyclized peptide 6 exhibited sevenfold more potent μ-opioid receptor agonistic activity in vitro. Interestingly, the cyclized analog 6 possessed an improved stability in the brain and an increased blood-brain barrier permeability compared to the parent peptide 0 and produced more potent analgesia after supraspinal or subcutaneous administration with improved duration of action of 4 h. In addition, antinociceptive tolerance of analog 6 was greatly reduced after subcutaneous injection compared to fentanyl, as was the rewarding effect, withdrawal reaction, and gastrointestinal inhibition.

40 keywords...

hide…