title: Endomorphin analogues with mixed μ-opioid (MOP) receptor agonism/δ-opioid (DOP) receptor antagonism and lacking β-arrestin2 recruitment activity.
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.
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cai
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Song
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Cai
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Ai-Leen
authors.initials: AL
authors.lastname: Lam
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Magiera
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Sunder
authors.initials: S
authors.lastname: Sekar
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Wyse
authors.affiliation: Tohoku Pharmaceutical University, 4-1 Komatsushima 4-chome, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.affiliation: Tohoku Pharmaceutical University, 4-1 Komatsushima 4-chome, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Medicinal Chemistry Group, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Science, Research Triangle Park, NC 27709, USA.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: maree.smith@uq.edu.au.
authors.forename: Maree T
authors.initials: MT
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D000071557:beta-Arrestins; D005576:Colforsin; D000242:Cyclic AMP
keywords: Analgesics; Dmt; Endomorphin-2; Opioid