Endomorphin analogues with mixed mu-opioid (MOP) receptor agonism/delta-opioid (DOP) receptor antagonism and lacking beta-arrestin2 recruitment activity

Cai, Jun, Song, Bowen, Cai, Yunxin, Ma, Yu, Lam, Ai-leen, Magiera, Julia, Sekar, Sunder, Wyse, Bruce D., Ambo, Akihiro, Sasaki, Yusuke, Lazarus, Lawrence H., Smith, Maree T. and Li, Tingyou (2014) Endomorphin analogues with mixed mu-opioid (MOP) receptor agonism/delta-opioid (DOP) receptor antagonism and lacking beta-arrestin2 recruitment activity. Biorganic and Medicinal Chemistry, 22 7: 2208-2219. doi:10.1016/j.bmc.2014.02.015


Author Cai, Jun
Song, Bowen
Cai, Yunxin
Ma, Yu
Lam, Ai-leen
Magiera, Julia
Sekar, Sunder
Wyse, Bruce D.
Ambo, Akihiro
Sasaki, Yusuke
Lazarus, Lawrence H.
Smith, Maree T.
Li, Tingyou
Title Endomorphin analogues with mixed mu-opioid (MOP) receptor agonism/delta-opioid (DOP) receptor antagonism and lacking beta-arrestin2 recruitment activity
Formatted title
Endomorphin analogues with mixed μ-opioid (MOP) receptor agonism/δ-opioid (DOP) receptor antagonism and lacking β-arrestin2 recruitment activity
Journal name Biorganic and Medicinal Chemistry   Check publisher's open access policy
ISSN 0968-0896
1464-3391
Publication date 2014-04-01
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.bmc.2014.02.015
Open Access Status
Volume 22
Issue 7
Start page 2208
End page 2219
Total pages 12
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon
Language eng
Formatted 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 = 0.13–0.81 nM), modest MOP-selectivity (Kiδ-opioid (DOP)/KiMOP = 3.5–316), and potent functional MOP agonism (GPI, IC50 = 0.274–249 nM) 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.
Keyword Endomorphin-2
Opioid analgesics
DMT
In vitro bioactivity
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID KY109RC01110801
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Pharmacy Publications
Centre for Integrated Preclinical Drug Development Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 4 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 23 Mar 2014, 03:13:17 EST by Professor Maree Smith on behalf of Centre for Integrated Preclinical Drug Development