Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies. IF(2019) 6,205

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

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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

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