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- Jun Cai, Bowen Song, Yunxin Cai, Yu Ma, Ai-Leen Lam, Julia Magiera, Sunder Sekar, Bruce D Wyse, Akihiro Ambo, Yusuke Sasaki, Lawrence H Lazarus, Maree T Smith, and Tingyou Li.
- School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
- Bioorg. Med. Chem. 2014 Apr 1;22(7):2208-19.
AbstractAnalogues of endomorphin (Dmt-Pro-Xaa-Xaa-NH2) modified at position 4 or at positions 4 and 3, and tripeptides (Dmt-Pro-Xaa-NH2) modified at position 3, with various phenylalanine analogues (Xaa=Trp, 1-Nal, 2-Nal, Tmp, Dmp, Dmt) were synthesized and their effects on in vitro opioid activity were investigated. Most of the peptides exhibited high μ-opioid (MOP) receptor binding affinity (KiMOP=0.13-0.81nM), modest MOP-selectivity (Kiδ-opioid (DOP)/KiMOP=3.5-316), and potent functional MOP agonism (GPI, IC50=0.274-249nM) without DOP and κ-opioid (KOP) receptor agonism. Among them, compounds 7 (Dmt-Pro-Tmp-Tmp-NH2) and 9 (Dmt-Pro-1-Nal-NH2) were opioids with potent mixed MOP receptor agonism/DOP receptor antagonism and devoid of β-arrestin2 recruitment activity. They may offer a unique template for the discovery of potent analgesics that produce less respiratory depression, less gastrointestinal dysfunction and that have a lower propensity to induce tolerance and dependence compared with morphine.Copyright © 2014 Elsevier Ltd. All rights reserved.
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