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

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Combining nonopioid pharmacophores with opioid ligands offers a promising strategy for pain management.
• Neurotensin (NT) and its receptor NTS1 are implicated in pain pathways, but NTS1 activation is linked to adverse effects.
• Selective targeting of the NTS2 receptor is preferred for safer pain therapeutics.

Purpose of the Study:

• To develop novel hybrid peptides by fusing the micro-/δ-opioid agonist tetrapeptide KGOP01 with neurotensin (NT) analogues.
• To investigate the receptor binding affinities and selectivity of these hybrid peptides for NTS1 and NTS2 receptors.
• To evaluate the antinociceptive efficacy and duration of the most promising hybrid peptide in a preclinical pain model.

Main Methods:

• Synthesis of hybrid peptides combining H-Dmt-d-Arg-Aba-β-Ala-NH2 (KGOP01) with modified NT(8-13) analogues.
• Introduction of modifications in the NT sequence, including a β3-homo amino acid at position 8 and Tyr11 substitutions.
• Assessment of receptor binding affinities (Ki) for NTS1 and NTS2 receptors.
• Evaluation of antinociceptive effects in mouse models.

Main Results:

• Peptide 7, a combination of β3hArg and Dmt, exhibited high NTS2 affinity (Ki = 3 pM) and good NTS1 affinity (Ki = 4 nM), achieving >1300-fold NTS2 selectivity.
• Analogue 9, containing (6-OH)Tic, showed high NTS2 affinity (Ki = 1.7 nM) and low NTS1 affinity (Ki = 4.7 microM), resulting in >2700-fold NTS2 selectivity.
• In mice, hybrid peptide 7 induced significant and prolonged antinociception lasting up to 8 hours, outperforming the parent opioid KGOP01.

Conclusions:

• Novel hybrid peptides combining opioid and neurotensin pharmacophores demonstrate potent and selective NTS2 receptor agonism.
• These hybrid peptides represent a promising new class of analgesics with improved safety profiles due to NTS2 selectivity.
• Hybrid peptide 7 shows significant potential for developing effective and long-lasting pain therapies.