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 (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 Tyr¹¹ substitutions. Combination of β³hArg 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-c

SUBMITTER: Gonzalez S 

PROVIDER: S-EPMC7667639 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature