2. Academic Validation
  3. Endomorphin analogues with mixed μ-opioid (MOP) receptor agonism/δ-opioid (DOP) receptor antagonism and lacking β-arrestin2 recruitment activity

Endomorphin analogues with mixed μ-opioid (MOP) receptor agonism/δ-opioid (DOP) receptor antagonism and lacking β-arrestin2 recruitment activity

  • Bioorg Med Chem. 2014 Apr 1;22(7):2208-19. doi: 10.1016/j.bmc.2014.02.015.
Jun Cai 1,  Bowen Song 1,  Yunxin Cai 1,  Yu Ma 1,  Ai-Leen Lam 2,  Julia Magiera 2,  Sunder Sekar 2,  Bruce D Wyse 2,  Akihiro Ambo 3,  Yusuke Sasaki 3,  Lawrence H Lazarus 4,  Maree T Smith 5,  Tingyou Li 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 2 Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 3 Tohoku Pharmaceutical University, 4-1 Komatsushima 4-chome, Aoba-ku, Sendai 981-8558, Japan.
  • 4 Medicinal Chemistry Group, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Science, Research Triangle Park, NC 27709, USA.
  • 5 Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: maree.smith@uq.edu.au.
  • 6 School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: l_tingyou@njmu.edu.cn.
PMID: 24613457 DOI: 10.1016/j.bmc.2014.02.015
Abstract

Analogues 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.

Keywords

Analgesics; Dmt; Endomorphin-2; Opioid.

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