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

Vivancos, Mélanie; Fanelli, Roberto; Besserer-Offroy, Élie; Beaulieu, Sabrina; Chartier, Magali; Resua-Rojas, Martin; Mona, Christine E.; Previti, Santo; Rémond, Emmanuelle; Longpré, Jean‐Michel; Cavelier, Florine; Sarret, Philippe

doi:10.1016/j.bbr.2021.113189

Cited by 8 publications

(10 citation statements)

References 88 publications

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“…98 The NTSR1 agonist PD149163 and the NTSR1 PAM PP-001 (structures not disclosed), both produced analgesia in acute and chronic pain models in rats. 99,100 As mentioned previously, both NTSR1 and NTSR2 agonists produce analgesia, however, the adverse effects of neurotensin such as hypothermia and hypotension are mediated via NTSR1 activation. 100 It was recently reported that the selective NTSR2 agonists JMV431 (63) produced antinociception in the tail-flick, formalin, and CFA tests in rats without inducing hypothermia.…”

Section: Nonsteroidal Anti-inflammatory Drugs (Nsaids)mentioning

confidence: 89%

“…The NTSR1 agonist PD149163 and the NTSR1 PAM PP-001 (structures not disclosed), both produced analgesia in acute and chronic pain models in rats. , As mentioned previously, both NTSR1 and NTSR2 agonists produce analgesia, however, the adverse effects of neurotensin such as hypothermia and hypotension are mediated via NTSR1 activation . It was recently reported that the selective NTSR2 agonists JMV431 ( 63 ) produced antinociception in the tail-flick, formalin, and CFA tests in rats without inducing hypothermia . CGX-1160 (structure not disclosed), a neurotensin A analogue, produced antinociception in a phase Ia clinical trial in patients with central neuropathic pain following spinal cord injury .…”

Section: Approaches To Develop Safer Ligands For New Pain Targetsmentioning

confidence: 90%

“…100 It was recently reported that the selective NTSR2 agonists JMV431 (63) produced antinociception in the tail-flick, formalin, and CFA tests in rats without inducing hypothermia. 100 CGX-1160 (structure not disclosed), a neurotensin A analogue, produced antinociception in a phase Ia clinical trial in patients with central neuropathic pain following spinal cord injury. 101 Thus, highly selective neurotensin receptor agonists are still a viable route to develop novel analgesics with low abuse potential.…”

Section: Nonsteroidal Anti-inflammatory Drugs (Nsaids)mentioning

confidence: 99%

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Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

et al. 2021

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Because of the problems associated with opioids, drug discovery efforts have been employed to develop opioids with reduced side effects using approaches such as biased opioid agonism, multifunctional opioids, and allosteric modulation of opioid receptors. Receptor targets such as adrenergic, cannabinoid, P2X3 and P2X7, NMDA, serotonin, and sigma, as well as ion channels like the voltage-gated sodium channels Nav1.7 and Nav1.8 have been targeted to develop novel analgesics. Several enzymes, such as soluble epoxide hydrolase, sepiapterin reductase, and MAGL/ FAAH, have also been targeted to develop novel analgesics. In this review, old and recent targets involved in pain signaling and compounds acting at these targets are summarized. In addition, strategies employed to reduce side effects, increase potency, and efficacy of opioids are also elaborated. This review should aid in propelling drug discovery efforts to discover novel analgesics.

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Section: Nonsteroidal Anti-inflammatory Drugs (Nsaids)mentioning

confidence: 89%

Section: Approaches To Develop Safer Ligands For New Pain Targetsmentioning

confidence: 90%

Section: Nonsteroidal Anti-inflammatory Drugs (Nsaids)mentioning

confidence: 99%

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Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

et al. 2021

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“…Numerous NTS 1 targeting ligands carrying the pharmacophore NT(8-13) hexapeptide sequence (H-Arg-Arg-Pro-Tyr-Ile-Leu-OH) , have been developed and studied in different types of peripheral tumors, such as colorectal cancer, prostate adenocarcinoma, breast cancer, or pancreatic cancer. − Contrarily, NTS 2 targeting peptides have been studied for their central opioid-independent analgesic potency. − Whereas very few analogues have been developed for imaging of peripheral tumors, NTS 2 ’s role in tumor development remains unclear and requires more investigations. Indeed, in prostate cancer, NTS 2 mRNA expression was found only in malignant well-differentiated (androgen receptors +) cell-lines .…”

Section: Introductionmentioning

confidence: 99%

“…8 − 12 Contrarily, NTS 2 targeting peptides have been studied for their central opioid-independent analgesic potency. 13 − 17 Whereas very few analogues have been developed for imaging of peripheral tumors, 18 NTS 2 ’s role in tumor development remains unclear and requires more investigations. Indeed, in prostate cancer, NTS 2 mRNA expression was found only in malignant well-differentiated (androgen receptors +) cell-lines.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2

Bodin

Previti

Jestin³

et al. 2023

ACS Omega

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Neurotensin receptor 2 (NTS 2 ) is a well-known mediator of central opioid-independent analgesia. Seminal studies have highlighted NTS 2 overexpression in a variety of tumors including prostate cancer, pancreas adenocarcinoma, and breast cancer. Herein, we describe the first radiometalated neurotensin analogue targeting NTS 2 . JMV 7488 (DOTA-(βAla) 2 -Lys-Lys-Pro-(D)Trp-Ile-TMSAla-OH) was prepared using solid-phase peptide synthesis, then purified, radiolabeled with 68 Ga and 111 In, and investigated in vitro on HT-29 cells and MCF-7 cells, respectively, and in vivo on HT-29 xenografts. [ 68 Ga]Ga-JMV 7488 and [ 111 In]In-JMV 7488 were quite hydrophilic (logD 7.4 = −3.1 ± 0.2 and −2.7 ± 0.2, respectively, p < 0.0001). Saturation binding studies showed good affinity toward NTS 2 (K D = 38 ± 17 nM for [ 68 Ga]Ga-JMV 7488 on HT-29 and 36 ± 10 nM on MCF-7 cells; K D = 36 ± 4 nM for [ 111 In]In-JMV 7488 on HT-29 and 46 ± 1 nM on MCF-7 cells) and good selectivity (no NTS 1 binding up to 500 nM). On cell-based evaluation, [ 68 Ga]Ga-JMV 7488 and [ 111 In]In-JMV 7488 showed high and fast NTS 2 -mediated internalization of 24 ± 5 and 25 ± 11% at 1 h for [ 111 In]In-JMV 7488, respectively, along with low NTS 2 -membrane binding (<8%).Efflux was as high as 66 ± 9% at 45 min for [ 68 Ga]Ga-JMV 7488 on HT-29 and increased for [ 111 In]In-JMV 7488 up to 73 ± 16% on HT-29 and 78 ± 9% on MCF-7 cells at 2 h. Maximum intracellular calcium mobilization of JMV 7488 was 91 ± 11% to that of levocabastine, a known NTS 2 agonist on HT-29 cells demonstrating the agonist behavior of JMV 7488. In nude mice bearing HT-29 xenograft, [ 68 Ga]Ga-JMV 7488 showed a moderate but promising significant tumor uptake in biodistribution studies that competes well with other nonmetalated radiotracers targeting NTS 2 . Significant uptake was also depicted in lungs. Interestingly, mice prostate also demonstrated [ 68 Ga]Ga-JMV 7488 uptake although the mechanism was not NTS 2 -mediated.

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

Cited by 8 publications

References 88 publications

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2

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

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