Opening the amino acid toolbox for peptide-based NTS2-selective ligands as promising lead compounds for pain management

Santo Previti, Michael Desgagné, Dirk Tourwé, Florine Cavelier, Philippe Sarret, Steven Ballet

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Chronic pain is one of the most critical health issues worldwide. Despite considerable efforts to find therapeutic alternatives, opioid drugs remain the gold standard for pain management. The administration of μ-opioid receptor (MOR) agonists is associated with detrimental and limiting adverse effects. Overall, these adverse effects strongly overshadow the effectiveness of opioid therapy. In this context, the development of neurotensin (NT) ligands has shown to be a promising approach for the management of chronic and acute pain. NT exerts its opioid-independent analgesic effects through the binding of two G protein-coupled receptors (GPCRs), NTS1 and NTS2. In the last decades, modified NT analogues have been proven to provide potent analgesia in vivo. However, selective NTS1 and nonselective NTS1/NTS2 ligands cause antinociception associated with hypothermia and hypotension, whereas selective NTS2 ligands induce analgesia without altering the body temperature and blood pressure. In light of this, various structure-activity relationship (SAR) studies provided findings addressing the binding affinity of ligands towards NTS2. Herein, we comprehensively review peptide-based NTS2-selective ligands as a robust alternative for future pain management. Particular emphasis is placed on SAR studies governing the desired selectivity and associated in vivo results.

Original languageEnglish
Article numbere3471
Pages (from-to)n/a
Number of pages17
JournalJournal of Peptide Science
Issue number6
Publication statusE-pub ahead of print - 11 Jan 2023

Bibliographical note

Funding Information:
The authors thank the Research Council of the Vrije Universiteit Brussel (VUB) for the financial support through the Strategic Research Program (SRP50). This work was supported by funding from the Canadian Institutes of Health Research (CIHR; FDN‐148413), the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canadian Foundation for Innovation (CFI). P.S. is the holder of Canada Research Chair Tier 1 in the Neurophysiopharmacology of Chronic Pain and a member of the Quebec Research Funds (FRQS)‐funded Quebec Pain Research Network (QPRN). M.D.’s PhD is funded by the FRQS.

Publisher Copyright:
© 2022 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.

Copyright 2023 Elsevier B.V., All rights reserved.


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