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

[Image: see text] 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 >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 (>2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.