Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies

Simon Gonzalez, Maria Dumitrascuta, Emilie Eiselt, Stevany Louis, Linda Kunze, Annalisa Blasiol, Melanie Vivancos, Santo Previti, Elke Dewolf, Charlotte Martin, Dirk Tourwe, Florine Cavelier, Louis Gendron, Philippe Sarret, Mariana Spetea, Steven Ballet

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the μ-/δ-opioid agonist tetrapeptide H-Dmt-d-Arg-Aba-β-Ala-NH2(KGOP01) was fused to NT(8-13) analogues. Since the NTS1 receptor has been linked to adverse effects, selective MOR-NTS2 ligands are preferred. Modifications were introduced within the native NT sequence, particularly a β3-homo amino acid in position 8 and Tyr11substitutions. Combination of β3hArg and Dmt led to peptide 7, a MOR agonist, showing the highest NTS2 affinity described to date (Ki= 3 pM) and good NTS1 affinity (Ki= 4 nM), providing a >1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue 9 also exhibited high NTS2 affinity (Ki= 1.7 nM), with low NTS1 affinity (Ki= 4.7 μM), resulting in an excellent NTS2 selectivity (>2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.

Original languageEnglish
Pages (from-to)12929-12941
Number of pages13
JournalJournal of medicinal chemistry
Issue number21
Publication statusPublished - 12 Nov 2020

Bibliographical note

Funding Information:
Drs. M. Bouvier, T. Hebert, S.A. Laporte, G. Pineyro, J.-C. Tardif, and E. Thorin (CQDM Team) are acknowledged for providing us with the Gαq biosensor. This work was supported by the Austrian Research Fund (FWF: I2463-B21 to M.S.), the Research Foundation Flanders (FWO Vlaanderen to S.B.), the Canadian Institutes of Health Research (CIHR) (FDN-148413 to P.S.), and the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2014-06358 to P.S.). P.S. holds a Canada Research Chair in Neurophysiopharmacology of Chronic Pain. E.E. was supported by a doctoral training award from the FRQ-S. M.D. was partly supported by the University of Innsbruck PhD stipend program.

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© 2020 American Chemical Society. All rights reserved.

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