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

Autor: Jean-Michel Longpré, Léa Théroux, Philippe Sarret, Michael Desgagné, Marc Sousbie, Lucie Chevillard, Jérôme Côté, Magali Chartier, Charles Rumsby, Lounès Haroune, Eric Marsault, Pierre-Luc Boudreault
Přispěvatelé: Université de Sherbrooke (UdeS), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Chevillard, Lucie
Rok vydání: 2021
Předmět:
Zdroj: Biomedicine & Pharmacotherapy, Vol 141, Iss, Pp 111861-(2021)
Biomedicine and Pharmacotherapy
Biomedicine and Pharmacotherapy, 2021, 141, pp.111861. ⟨10.1016/j.biopha.2021.111861⟩
ISSN: 1950-6007
0753-3322
DOI: 10.1016/j.biopha.2021.111861⟩
Popis: International audience; 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.
Databáze: OpenAIRE
Externí odkaz: