Title | Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects |
Authors | Zhang, Yu-zhe Wang, Meng-meng Wang, Si-yu Wang, Xiao-fang Yang, Wen-jiao Zhao, Ya-nan Han, Feng-tong Zhang, Yao Gu, Ning Wang, Chang-lin |
Affiliation | Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150001, Peoples R China Jiangxi Univ Chinese Med, Nanchang 330004, Jiangxi, Peoples R China Peking Univ, Stake Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China |
Keywords | BLOOD-BRAIN-BARRIER PLACE PREFERENCE RESPONSES NERVE INJURY MODEL NEUROPATHIC PAIN PEPTIDE ANALOGS IN-VITRO CHIMERIC PEPTIDE NEUROPEPTIDE FF RECEPTOR TOLERANCE |
Issue Date | 25-Nov-2021 |
Publisher | JOURNAL OF MEDICINAL CHEMISTRY |
Abstract | Endomorphins (EMs) are potent pharmaceuticals for the treatment of pain. Herein, we investigated several novel EM analogues with multiple modifications and oligoarginine conjugation. Our results showed that analogues 1-6 behaved as potent mu-opioid agonists and enhanced stability and lipophilicity. Analogues 5 and 6 administered centrally and peripherally induced significant and prolonged antinociceptive effects in acute pain. Both analogues also produced long-acting antiallodynic effects against neuropathic and inflammatory pain. Furthermore, they showed a reduced acute antinociceptive tolerance. Analogue 6 decreased the extent of chronic antinociceptive tolerance, and analogue 5 exhibited no tolerance at the supraspinal level. Particularly, they displayed nontolerance-forming antinociception at the peripheral level. In addition, analogues 5 and 6 exhibited reduced or no opioid-like side effects on gastrointestinal transit, conditioned place preference (CPP), and motor impairment. The present investigation established that multiple modifications and oligoarginine-vector conjugation of EMs would be helpful in developing novel analgesics with fewer side effects. |
URI | http://hdl.handle.net/20.500.11897/638041 |
ISSN | 0022-2623 |
DOI | 10.1021/acs.jmedchem.1c01631 |
Indexed | SCI(E) |
Appears in Collections: | 天然药物与仿生药物国家重点实验室 |