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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-NH 2 ( 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 β 3 -homo amino acid in position 8 and Tyr 11 substitutions. Combination of β 3 hArg and Dmt led to peptide 7 , a MOR agonist, showing the highest NTS2 affinity described to date ( K  i = 3 pM) and good NTS1 affinity ( K  i = 4 nM), providing a &gt;1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue 9 also exhibited high NTS2 affinity ( K  i = 1.7 nM), with low NTS1 affinity ( K  i = 4.7 μM), resulting in an excellent NTS2 selectivity (&gt;2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.

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