Pharmacodynamic and pharmacokinetic profiles of a neurotensin receptor type 2 (NTS2) analgesic macrocyclic analog.

Abstract

The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr11 residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys8 and Trp11 to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (Ki 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t1/2 > 24 h) compared with NT (t1/2 ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED50 = 4.6 µg/kg) and tonic (ED50 = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.

• Authors: Magali Chartier, Michael Desgagné, Marc Sousbie, Charles Rumsby, Lucie Chevillard, Léa Théroux, Lounès Haroune, Jérôme Côté, Jean-Michel Longpré, Pierre-Luc Boudreault, Éric Marsault, Philippe Sarret
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 141 Pg. 111861 (Sep 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 34229249 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Analgesics, Non-Narcotic
• Analgesics, Opioid
• Macrocyclic Compounds
• Ntsr2 protein, rat
• Receptors, Neurotensin
• neurotensin type 1 receptor
• Morphine

Topics

• Analgesics, Non-Narcotic (chemical synthesis, pharmacokinetics, pharmacology)
• Analgesics, Opioid (pharmacology)
• Animals
• CHO Cells
• Cricetinae
• Cricetulus
• Cyclization
• Dose-Response Relationship, Drug
• Drug Design
• Drug Synergism
• Hyperalgesia (drug therapy, etiology)
• Inflammation (complications, drug therapy)
• Macrocyclic Compounds (chemical synthesis, pharmacokinetics, pharmacology)
• Male
• Morphine (pharmacology)
• Pain Measurement (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Neurotensin (drug effects)
• Substrate Specificity