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 (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.
Highlights
Pain remains a major global health concern affecting the worldwide population
We have reported the design, synthesis, in vitro/in vivo pharmacology, and structure−activity relationship (SAR) of new OP-NT multitarget peptides, which, unlike the single OP-NT chimeric structure known to date, PK20 derived from endomorphin-2, are associating a dermorphin derivative, KGOP01 as the opioid pharmacophore, and several NT analogues
We have shown that fusion of the OP and NT pharmacophores appeared to largely alter the interaction with the opioid receptors with overall decreased binding at the DOR and KOR while maintaining a good affinity at the MOR
Summary
Pain remains a major global health concern affecting the worldwide population. Moderate to severe pain is nowadays treated by opioid analgesics such as morphine, oxycodone, and fentanyl that activate the μ-opioid receptor (MOR). Arg substitutions by Lys residues did not induce the expected improvement, as observed with NT analogues alone.11 These hybrids generally showed a slightly reduced binding at NTS1 but different effects were noticed at NTS2, namely, decreased (for 8 vs 7 and 10 vs 9) or similar affinity (for 12 vs 11). The in vitro functional NT profile of the new OP-NT hybrid peptides was assessed To this end, the NTS1 canonical signaling pathway was monitored by a BRET-based Gαq activation assay using human embryonic kidney 293 (HEK293) cells stably expressing the human NTS1.31 Even though the corresponding modifications within the NT sequence did reduce NTS1 binding for most analogues, their agonistic activity at the receptor remained similar to the initial.
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