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
Subject 1303 Biochemistry
1313 Molecular Medicine
1312 Molecular Biology
3003 Pharmaceutical Science
3002 Drug Discovery
1308 Clinical Biochemistry
1605 Organic Chemistry
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 mu-opioid (MOP) receptor binding affinity (K-iMOP = 0.13-0.81 nM), modest MOP-selectivity (Ki delta-opioid (DOP)/K-iMOP = 3.5-316), and potent functional MOP agonism (GPI, IC50 = 0.274-249 nM) without DOP and kappa-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 beta-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. (C) 2014 Elsevier Ltd. All rights reserved.
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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Created: Sun, 23 Mar 2014, 03:13:17 EST by Professor Maree Smith on behalf of Centre for Integrated Preclinical Drug Development