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

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Abstract

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.

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Gonzalez, S., Dumitrascuta, M., Eiselt, E., Louis, S., Kunze, L., Blasiol, A., … Ballet, S. (2020). Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies. Journal of Medicinal Chemistry, 63(21), 12929–12941. https://doi.org/10.1021/acs.jmedchem.0c01376

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