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

Chartier, Magali; Desgagné, Michael; Sousbie, Marc; Rumsby, Charles; Chevillard, L; Théroux, Léa; Haroune, Lounès; Côté, Jérôme; Longpré, Jean‐Michel; Boudreault, Pierre‐Luc; Marsault, Éric; Sarret, Philippe

doi:10.1016/j.biopha.2021.111861

Cited by 9 publications

(6 citation statements)

References 107 publications

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“…Among these, promising results were obtained with the nonselective cyclic NT8–13 analogue JMV2012 (c[Lys‐Lys‐Pro‐Tyr‐Ile‐Leu‐Lys‐Lys‐Pro‐Tyr‐Ile‐Leu]): Indeed, this cyclic analogue showed potent antinociceptive and hypothermic effects after peripheral administration, suggesting an appreciable crossing of the BBB 93 . More recently, the development of the first NTS2‐selective macrocyclic ligand has been reported 96 . Compound CR‐01‐64 ( 75 ) (Figure 4) bears an N ‐allylated Trp 11 residue, which is essential both for selectivity towards NTS2 and for the cyclization.…”

Section: Towards Peptide‐based Nts2 Ligandsmentioning

confidence: 99%

“…93 More recently, the development of the first NTS2-selective macrocyclic ligand has been reported. 96 Compound CR-01-64 (75) (Figure 4) bears an N-allylated In parallel to the development of the first NTS2-selective macrocycle, a meticulous and rational SAR study led to the identification of structurally novel NTS2-selective macrocyclic NT analogues. 97 Initially, an alanine scan and various substitutions and deletions were carried out, from which the truncated linear NT analogue NT8-12…”

Section: Macrocyclic Analoguesmentioning

confidence: 99%

“…The intrathecal injection of an F I G U R E 4 Chemical structure, binding affinities, and SI of macrocycle 75. Adapted from research articles published by Chartier and co-workers96…”

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confidence: 99%

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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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Section: Towards Peptide‐based Nts2 Ligandsmentioning

confidence: 99%

Section: Macrocyclic Analoguesmentioning

confidence: 99%

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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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“…NT and NTSR1 are then promising candidates for clinical screening for gastrointestinal cancers because of their overexpression in these cancers, and are promising targets because the inhibition of NTSR1 expression or the knockdown of the NTS1 gene decreases oncotic MMP-9 expression and activity (Dong et al, 2017;Sánchez and Coveñas, 2021). Finally, NT has central opioid-independent anti-nociceptive effects, leading to improved therapeutic management of pain (Chartier et al, 2021).…”

Section: Contulakin-g/neurotensin: Neurotensin Receptorsmentioning

confidence: 99%

Structural and Functional Diversity of Animal Toxins Interacting With GPCRs

Baelen

Robin

Kessler

et al. 2022

Front. Mol. Biosci.

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Peptide toxins from venoms have undergone a long evolutionary process allowing host defense or prey capture and making them highly selective and potent for their target. This has resulted in the emergence of a large panel of toxins from a wide diversity of species, with varied structures and multiple associated biological functions. In this way, animal toxins constitute an inexhaustible reservoir of druggable molecules due to their interesting pharmacological properties. One of the most interesting classes of therapeutic targets is the G-protein coupled receptors (GPCRs). GPCRs represent the largest family of membrane receptors in mammals with approximately 800 different members. They are involved in almost all biological functions and are the target of almost 30% of drugs currently on the market. Given the interest of GPCRs in the therapeutic field, the study of toxins that can interact with and modulate their activity with the purpose of drug development is of particular importance. The present review focuses on toxins targeting GPCRs, including peptide-interacting receptors or aminergic receptors, with a particular focus on structural aspects and, when relevant, on potential medical applications. The toxins described here exhibit a great diversity in size, from 10 to 80 amino acids long, in disulfide bridges, from none to five, and belong to a large panel of structural scaffolds. Particular toxin structures developed here include inhibitory cystine knot (ICK), three-finger fold, and Kunitz-type toxins. We summarize current knowledge on the structural and functional diversity of toxins interacting with GPCRs, concerning first the agonist-mimicking toxins that act as endogenous agonists targeting the corresponding receptor, and second the toxins that differ structurally from natural agonists and which display agonist, antagonist, or allosteric properties.

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“…Semipeptidic macrocycles display a variety of biological activities, such as antibacterial, antifungal, anticancer, and antiviral activity . Moreover, peptide macrocyclization is a well-established tool to modulate binding affinity, selectivity, signaling profile, , and PK-ADME properties , of pharmacologically relevant peptidic ligands. Some synthetic macrocycles have even been used to target previously thought “undruggable” protein–protein interactions , as these peptides are often considered to fit in a chemical space in-between the biologics and small molecules .…”

Section: Introductionmentioning

confidence: 99%

Insights on Structure–Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles

Ly,

Desgagné,

Nguyen

et al. 2024

J. Med. Chem.

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Macrocycles have recognized therapeutic potential, but their limited cellular permeability can hinder their development as oral drugs. To better understand the structure−permeability relationship of heterocycle-containing, semipeptidic macrocycles, a library was synthesized. These compounds were created by developing two novel reactions described herein: the reduction of activated oximes by LiBH 4 and the aqueous reductive mono-N-alkylation of aldehydes using catalytic SmI 2 and stoichiometric Zn. The permeability of the macrocycles was evaluated through a parallel artificial membrane permeability assay (PAMPA), and the results indicated that macrocycles with a furan incorporated into the structure have better passive permeability than those with a pyrrole moiety. Compounds bearing a 2,5-disubstituted pyrrole (endo orientation) were shown to be implicated in intramolecular H-bonds, enhancing their permeability. This study highlighted the impact of heterocycles moieties in semipeptides, creating highly permeable macrocycles, thus showing promising avenues for passive diffusion of drugs beyond the rule-of-five chemical space.

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

Cited by 9 publications

References 107 publications

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

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

Structural and Functional Diversity of Animal Toxins Interacting With GPCRs

Insights on Structure–Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles

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