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

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