NTS2-selective neurotensin mimetics with tetrahydrofuran amino acids

Simeth, Nadja A.; Bause, Manuel; Dobmeier, Michael; Kling, Ralf C.; Lachmann, Daniel; Hübner, Harald; Einsiedel, Jürgen; Gmeiner, Peter; König, Burkhard

doi:10.1016/j.bmc.2016.10.039

Cited by 8 publications

(7 citation statements)

References 71 publications

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“…The crucial role played by the tyrosine residue at position 11 in macrocyclic structure will also require further study. Indeed, as previously demonstrated using unnatural amino acids, ,− the alanine scan also reveals that modification of NT at Tyr 11 is detrimental for NTS1, thus increasing the selectivity toward NTS2.…”

Section: Results and Discussionsupporting

confidence: 56%

“…To date, different chemical strategies have been used to improve receptor binding affinity and selectivity toward NTS2 as well as peptide stability and permeability. Among these approaches, substitution of the tyrosine residue in position 11 by natural (lysine) or unnatural amino acids ( d -Trp, d -Tyr, ( R )-Nal, d -3,1-Nal, 6-OH-Tic, Dmt, m Tyr, N- h Tyr, ( R )-FPTyr, and (R Trans )TAA(OH)) has been found to favor NTS2 selectivity. ,− Accordingly, molecular dynamics simulations revealed that conformational changes and flexibility in Tyr 11 are required for NTS1 activation by NT, thus reinforcing the crucial role played by Tyr 11 in NTS1/NTS2 selectivity …”

Section: Introductionmentioning

confidence: 99%

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Design, Structural Optimization, and Characterization of the First Selective Macrocyclic Neurotensin Receptor Type 2 Non-opioid Analgesic

et al. 2021

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Neurotensin (NT) receptor type 2 (NTS2) represents an attractive target for the development of new NT-based analgesics. Here, we report the synthesis and functional in vivo characterization of the first constrained NTS2-selective macrocyclic NT analog. While most chemical optimization studies rely on the NT(8-13) fragment, we focused on NT(7-12) as a scaffold to design NTS2-selective macrocyclic peptides. Replacement of Ile 12 by Leu, and Pro 7 /Pro 10 by allylglycine residues followed by cyclization via ring-closing metathesis led to macrocycle 4, which exhibits good affinity for NTS2 (50 nM), high selectivity over NTS1 (>100 μM), and improved stability compared to . In vivo profiling in rats reveals that macrocycle 4 produces potent analgesia in three distinct rodent pain models, without causing the undesired effects associated with NTS1 activation. We further provide evidence of its nonopioid antinociceptive activity, therefore highlighting the strong therapeutic potential of NTS2-selective analogs for the management of acute and chronic pain.

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Section: Results and Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Design, Structural Optimization, and Characterization of the First Selective Macrocyclic Neurotensin Receptor Type 2 Non-opioid Analgesic

et al. 2021

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“…These results are in accordance with previous studies supporting the importance of aromatic residues in the structure–activity relationship for the affinity toward NT receptors. − The extension of the aromaticity and changes in side chain orientation seem to favor hNTS2 selectivity. Indeed, substitution of the l -Tyr in position 11 by unnatural d -amino acids such as d -α-naphthylalanine is well-tolerated by NTS2 and leads to substantial loss in NTS1 binding. − Furthermore, high NTS2 selectivity has also been observed with a peptide–peptoid hybrid resulting from replacement of Tyr with N -homotyramine , and more recently with tetrahydrofuran amino acids …”

Section: Discussionmentioning

confidence: 99%

Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues

et al. 2017

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Neurotensin exerts potent analgesia by acting at both NTS1 and NTS2 receptors, whereas NTS1 activation also results in other physiological effects such as hypotension and hypothermia. Here, we used molecular modeling approach to design highly selective NTS2 ligands by investigating the docking of novel NT[8-13] compounds at both NTS1 and NTS2 sites. Molecular dynamics simulations revealed an interaction of the Tyr residue of NT[8-13] with an acidic residue (Glu) located in the ECL2 of hNTS2 or with a basic residue (Arg) at the same position in hNTS1. The importance of the residue at position 11 for NTS1/NTS2 selectivity was further demonstrated by the design of new NT analogues bearing basic (Lys, Orn) or acid (Asp or Glu) function. As predicted by the molecular dynamics simulations, binding of NT[8-13] analogues harboring a Lys exhibited higher affinity toward the hNTS1-R212E mutant receptor, in which Arg212 was substituted by the negatively charged Glu residue.

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“…Accordingly, l -2-methylphenylalanine 2c is used as chiral synthon within the synthesis of endomorphin-2 analogues of improved affinities for μ-opioid receptors, while l -3-methylphenylalanine 2g can be integrated within cathepsin B inhibitors , involved in the pathogenesis of several diseases, most notably Alzheimer’s disease (AD) and cancer . Bromo-substituted phenylalanines 2a and 2i play key roles within the synthesis of NTS2 selective neurotensin ligands used for reducing tonic pain sensitivity or within the production of several biarylalanines and biaryl-bridged macrocyclic peptides . The p -methoxy- l -phenylalanine 2l can be found in the structure of l -thyronine (product of thyroid hormone metabolism), as well as of a key intermediate for the α-blocker tamsulosin .…”

Section: Resultsmentioning

confidence: 99%

Engineered, Scalable Production of Optically Pure l-Phenylalanines Using Phenylalanine Ammonia-Lyase from Arabidopsis thaliana

et al. 2022

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An efficient preparative-scale synthetic procedure of l-phenylalanine derivatives has been developed using mutant variants of phenylalanine ammonia-lyase from Arabidopsis thaliana (AtPAL). After rigorous reaction engineering, the AtPAL-catalyzed hydroamination reaction of cinnamic acids provided several unnatural amino acids of high synthetic value, such as (S)-m- and (S)-p-methoxyphenylalanine; (S)-o- and (S)-m-methylphenylalanine; and (S)-o- and (S)-p-bromophenylalanine at preparative scale, significantly surpassing the catalytic efficiency in terms of conversions and yields of the previously reported PcPAL-based biotransformations. The AtPAL variants tolerated high substrate and product concentrations, representing an important extension of the PAL-toolbox, while the engineered biocatalytic procedures of improved E-factor and space-time yields fulfill the requirements of sustainable and green chemistry, providing facile access to valuable amino acid building blocks.

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NTS2-selective neurotensin mimetics with tetrahydrofuran amino acids

Cited by 8 publications

References 71 publications

Design, Structural Optimization, and Characterization of the First Selective Macrocyclic Neurotensin Receptor Type 2 Non-opioid Analgesic

Design, Structural Optimization, and Characterization of the First Selective Macrocyclic Neurotensin Receptor Type 2 Non-opioid Analgesic

Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues

Engineered, Scalable Production of Optically Pure l-Phenylalanines Using Phenylalanine Ammonia-Lyase from Arabidopsis thaliana

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