Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog

Tétreault, Pascal; Besserer-Offroy, Élie; Brouillette, Rebecca L.; René, Adeline; Murza, Alexandre; Fanelli, Roberto; Kirby, Karyn; Parent, Alexandre J.; Dubuc, Isabelle; Beaudet, Nicolas; Côté, Jérôme; Longpré, Jean‐Michel; Martínez, Jean; Cavelier, Florine; Sarret, Philippe

doi:10.1016/j.ejphar.2020.173174

Cited by 10 publications

(14 citation statements)

References 94 publications

(109 reference statements)

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“…However, this substitution greatly improved the degradation profile of JMV5170 with a more than 150-fold increase in plasma half-life (> 20 hours), compared to JMV449 (< 10 min). This was previously observed, in a lesser extent, with a NT(8-13) analog bearing a Sip in position 10 but lacking the reduced amine bond between Lys 8 -Lys 9 (namely, JMV2009; H-Lys-Lys-Sip-Tyr-Ile-Leu-OH) [36,58]. Indeed, JMV2009 displayed a slightly reduced affinity at both NTS1 and NTS2 receptor sites but an extended ex-vivo plasma half-life when compared to the full-length NT peptide, undoubtedly mediated by a reduced recognition by metallo-endopeptidases.…”

Section: ) Analogssupporting

confidence: 59%

“…The analgesic response of JMV5296 in the formalin pain test is comparable to the response elicited by an i.t. injection of either JMV2007 or JMV2009, two non-selective NT agonists [36,61]. Nevertheless, in contrast to JMV2007, JMV5296 did not decrease the nociceptive behaviors in the acute phase.…”

Section: Jmv5296 Alleviates Tonic and Chronic Inflammatory Painmentioning

confidence: 77%

“…JMV2009 [36] and JMV2007 [61]), suggesting that in the case of multiple chemical modifications, the addition of the reduced bond did not confer a better efficacy in this pain paradigm. Interestingly, the response of these new NT derivatives was comparable to the one produced by equimolar dose of i.t.…”

Section: Central Delivery Of Nt(8-13) Analogs With a Reduced Amine Bo...mentioning

confidence: 93%

“…This isostere unnatural amino acid of proline introduced at position 10 protects against the second enzymatic cleavage. We recently demonstrated that the replacement of Pro 10 by Sip 10 did not affect the compound's structure [57] or receptor binding affinity, however, this modification slightly increased its resistance toward proteases [36,58].…”

Section: Rational Design Of Nt(8-13) Analogsmentioning

confidence: 99%

“…While analgesia in acute, tonic, and chronic pain paradigms was demonstrated to be mediated by the activation of both receptors [24,25,28,[34][35][36], only NTS1 activation was associated with hypotension [14,37] and hypothermia [38].…”

Section: Introductionmentioning

confidence: 99%

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

Vivancos

Fanelli

Besserer-Offroy

et al. 2021

Behavioural Brain Research

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Highlights § Incorporation of reduced amide bond, silaproline and TMSAla in NT(8-13) resulted in JMV5296, a 25-fold NTS2-selective analog. § Combination of these three chemical modifications increased resistance toward proteases having a plasma stability over 20 hours. § Intrathecal injection of JMV5296 induced potent antinociception in acute, tonic and chronic inflammatory pain models. § Central delivery of JMV5296 had no impact on body temperature.

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Section: ) Analogssupporting

confidence: 59%

Section: Jmv5296 Alleviates Tonic and Chronic Inflammatory Painmentioning

confidence: 77%

Section: Central Delivery Of Nt(8-13) Analogs With a Reduced Amine Bo...mentioning

confidence: 93%

Section: Rational Design Of Nt(8-13) Analogsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Vivancos

Fanelli

Besserer-Offroy

et al. 2021

Behavioural Brain Research

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

Previti

Desgagné

Tourwé

et al. 2023

Journal of Peptide Science

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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.

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Data set describing the in vitro biological activity of JMV2009, a novel silylated neurotensin(8–13) analog

et al. 2020

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Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog

Cited by 10 publications

References 94 publications

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

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

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

Data set describing the in vitro biological activity of JMV2009, a novel silylated neurotensin(8–13) analog

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