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

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 (<b>KGOP01</b>) was fused to <b>NT(8-13)</b> 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 Tyr¹¹ substitutions. Combination of β³hArg and Dmt led to peptide <b>7</b>, a MOR agonist, showing the highest NTS2 affinity described to date (<i>K</i>_i = 3 pM) and good NTS1 affinity (<i>K</i>_i = 4 nM), providing a >1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue <b>9</b> also exhibited high NTS2 affinity (<i>K</i>_i = 1.7 nM), with low NTS1 affinity (<i>K</i>_i = 4.7 μM), resulting in an excellent NTS2 selectivity (>2700). In mice, hybrid <b>7</b> produced significant and prolonged antinociception (up to 8 h), as compared to the <b>KGOP01</b> opioid parent compound.