Metabolically stable neurotensin analogs exert potent and long-acting analgesia without hypothermia

Autor: Martin Resua-Rojas, Magali Chartier, Christine E. Mona, Philippe Sarret, Jean-Michel Longpré, Florine Cavelier, Emmanuelle Rémond, Roberto Fanelli, Élie Besserer-Offroy, Santo Previti, Sabrina Beaulieu, Mélanie Vivancos
Přispěvatelé: Université de Sherbrooke (UdeS), University of California [Los Angeles] (UCLA), University of California, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2020
Předmět:
Zdroj: Behavioural Brain Research
Behavioural Brain Research, Elsevier, 2021, 405, pp.113189. ⟨10.1016/j.bbr.2021.113189⟩
ISSN: 1872-7549
0166-4328
Popis: The endogenous tridecapeptide neurotensin (NT) has emerged as an important inhibitory modulator of pain transmission, exerting its analgesic action through the activation of the G protein-coupled receptors, NTS1 and NTS2. Whereas both NT receptors mediate the analgesic effects of NT, NTS1 activation also produces hypotension and hypothermia, which may represent obstacles for the development of new pain medications. In the present study, we implemented various chemical strategies to improve the metabolic stability of the biologically active fragment NT(8-13) and assessed their NTS1/NTS2 relative binding affinities. We then determined their ability to reduce the nociceptive behaviors in acute, tonic, and chronic pain models and to modulate blood pressure and body temperature. To this end, we synthesized a series of NT(8-13) analogs carrying a reduced amide bond at Lys8-Lys9 and harboring site-selective modifications with unnatural amino acids, such as silaproline (Sip) and trimethylsilylalanine (TMSAla). Incorporation of Sip and TMSAla respectively in positions 10 and 13 of NT(8-13) combined with the Lys8-Lys9 reduced amine bond (JMV5296) greatly prolonged the plasma half-life time over 20 hours. These modifications also led to a 25-fold peptide selectivity toward NTS2. More importantly, central delivery of JMV5296 was able to induce a strong antinociceptive effect in acute (tail-flick), tonic (formalin), and chronic inflammatory (CFA) pain models without inducing hypothermia. Altogether, these results demonstrate that the chemically-modified NT(8-13) analog JMV5296 exhibits a better therapeutic profile and may thus represent a promising avenue to guide the development of new stable NT agonists and improve pain management.
This is the post-print (accepted) version of the following article: Vivancos M, et al. (2021), Behav Brain Res. doi: 10.1016/j.bbr.2021.113189, which has been accepted and published in final form at https://www.sciencedirect.com/science/article/pii/S0166432821000772
Databáze: OpenAIRE
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