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-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
(Ki = 3 pM) and good NTS1 affinity (Ki = 4 nM), providing a >1300-fold NTS2 selectivity.
The (6-OH)­Tic-containing analogue 9 also exhibited high
NTS2 affinity (Ki = 1.7 nM), with low
NTS1 affinity (Ki = 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.