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

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; Tingyou Li

doi:10.1016/j.bmc.2014.02.015

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. Epub 2014 Feb 24.

Authors

Jun Cai¹, Bowen Song¹, Yunxin Cai¹, Yu Ma¹, Ai-Leen Lam², Julia Magiera², Sunder Sekar², Bruce D Wyse², Akihiro Ambo³, Yusuke Sasaki³, Lawrence H Lazarus⁴, Maree T Smith⁵, Tingyou Li⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arrestins / metabolism*
Colforsin / antagonists & inhibitors
Colforsin / pharmacology
Cyclic AMP / metabolism
Guinea Pigs
HEK293 Cells
Humans
Male
Mice
Molecular Structure
Oligopeptides / chemical synthesis
Oligopeptides / chemistry
Oligopeptides / pharmacology*
Rats
Rats, Sprague-Dawley
Receptors, Opioid, delta / antagonists & inhibitors*
Receptors, Opioid, mu / agonists*
beta-Arrestins

Substances

Arrestins
Oligopeptides
Receptors, Opioid, delta
Receptors, Opioid, mu
beta-Arrestins
Colforsin
Cyclic AMP