Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies

Simon Gonzalez; Maria Dumitrascuta; Emilie Eiselt; Stevany Louis; Linda Kunze; Annalisa Blasiol; Melanie Vivancos; Santo Previti; Elke Dewolf; Charlotte Martin; Dirk Tourwe; Florine Cavelier; Louis Gendron; Philippe Sarret; Mariana Spetea; Steven Ballet

doi:10.1021/acs.jmedchem.0c01376

Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies

Simon Gonzalez, Maria Dumitrascuta, Emilie Eiselt, Stevany Louis, Linda Kunze, Annalisa Blasiol, Melanie Vivancos, Santo Previti, Elke Dewolf, Charlotte Martin, Dirk Tourwe, Florine Cavelier, Louis Gendron, Philippe Sarret, Mariana Spetea, Steven Ballet

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21 Citaten (Scopus)

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Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the μ-/δ-opioid agonist tetrapeptide H-Dmt-d-Arg-Aba-β-Ala-NH₂(KGOP01) was fused to NT(8-13) analogues. Since the NTS1 receptor has been linked to adverse effects, selective MOR-NTS2 ligands are preferred. Modifications were introduced within the native NT sequence, particularly a β³-homo amino acid in position 8 and Tyr¹¹substitutions. Combination of β³hArg and Dmt led to peptide 7, a MOR agonist, showing the highest NTS2 affinity described to date (K_i= 3 pM) and good NTS1 affinity (K_i= 4 nM), providing a >1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue 9 also exhibited high NTS2 affinity (K_i= 1.7 nM), with low NTS1 affinity (K_i= 4.7 μM), resulting in an excellent NTS2 selectivity (>2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.

Originele taal-2	English
Pagina's (van-tot)	12929-12941
Aantal pagina's	13
Tijdschrift	Journal of medicinal chemistry
Volume	63
Nummer van het tijdschrift	21
DOI's	https://doi.org/10.1021/acs.jmedchem.0c01376
Status	Published - 12 nov. 2020

Bibliografische nota

Funding Information:
Drs. M. Bouvier, T. Hebert, S.A. Laporte, G. Pineyro, J.-C. Tardif, and E. Thorin (CQDM Team) are acknowledged for providing us with the Gαq biosensor. This work was supported by the Austrian Research Fund (FWF: I2463-B21 to M.S.), the Research Foundation Flanders (FWO Vlaanderen to S.B.), the Canadian Institutes of Health Research (CIHR) (FDN-148413 to P.S.), and the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2014-06358 to P.S.). P.S. holds a Canada Research Chair in Neurophysiopharmacology of Chronic Pain. E.E. was supported by a doctoral training award from the FRQ-S. M.D. was partly supported by the University of Innsbruck PhD stipend program.

Publisher Copyright:
© 2020 American Chemical Society. All rights reserved.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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Gonzalez, S., Dumitrascuta, M., Eiselt, E., Louis, S., Kunze, L., Blasiol, A., Vivancos, M., Previti, S., Dewolf, E., Martin, C., Tourwe, D., Cavelier, F., Gendron, L., Sarret, P., Spetea, M., & Ballet, S. (2020). Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies. Journal of medicinal chemistry, 63(21), 12929-12941. https://doi.org/10.1021/acs.jmedchem.0c01376

@article{b55657873be04e488dac9092ed30584e,

title = "Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies",

abstract = "Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the μ-/δ-opioid agonist tetrapeptide H-Dmt-d-Arg-Aba-β-Ala-NH2(KGOP01) was fused to NT(8-13) analogues. Since the NTS1 receptor has been linked to adverse effects, selective MOR-NTS2 ligands are preferred. Modifications were introduced within the native NT sequence, particularly a β3-homo amino acid in position 8 and Tyr11substitutions. Combination of β3hArg and Dmt led to peptide 7, a MOR agonist, showing the highest NTS2 affinity described to date (Ki= 3 pM) and good NTS1 affinity (Ki= 4 nM), providing a >1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue 9 also exhibited high NTS2 affinity (Ki= 1.7 nM), with low NTS1 affinity (Ki= 4.7 μM), resulting in an excellent NTS2 selectivity (>2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.",

author = "Simon Gonzalez and Maria Dumitrascuta and Emilie Eiselt and Stevany Louis and Linda Kunze and Annalisa Blasiol and Melanie Vivancos and Santo Previti and Elke Dewolf and Charlotte Martin and Dirk Tourwe and Florine Cavelier and Louis Gendron and Philippe Sarret and Mariana Spetea and Steven Ballet",

note = "Funding Information: Drs. M. Bouvier, T. Hebert, S.A. Laporte, G. Pineyro, J.-C. Tardif, and E. Thorin (CQDM Team) are acknowledged for providing us with the Gαq biosensor. This work was supported by the Austrian Research Fund (FWF: I2463-B21 to M.S.), the Research Foundation Flanders (FWO Vlaanderen to S.B.), the Canadian Institutes of Health Research (CIHR) (FDN-148413 to P.S.), and the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2014-06358 to P.S.). P.S. holds a Canada Research Chair in Neurophysiopharmacology of Chronic Pain. E.E. was supported by a doctoral training award from the FRQ-S. M.D. was partly supported by the University of Innsbruck PhD stipend program. Publisher Copyright: {\textcopyright} 2020 American Chemical Society. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2020",

month = nov,

day = "12",

doi = "10.1021/acs.jmedchem.0c01376",

language = "English",

volume = "63",

pages = "12929--12941",

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Gonzalez, S, Dumitrascuta, M, Eiselt, E, Louis, S, Kunze, L, Blasiol, A, Vivancos, M, Previti, S, Dewolf, E, Martin, C , Tourwe, D, Cavelier, F, Gendron, L, Sarret, P, Spetea, M & Ballet, S 2020, 'Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies', Journal of medicinal chemistry, vol. 63, nr. 21, blz. 12929-12941. https://doi.org/10.1021/acs.jmedchem.0c01376

TY - JOUR

T1 - Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies

AU - Gonzalez, Simon

AU - Dumitrascuta, Maria

AU - Eiselt, Emilie

AU - Louis, Stevany

AU - Kunze, Linda

AU - Blasiol, Annalisa

AU - Vivancos, Melanie

AU - Previti, Santo

AU - Dewolf, Elke

AU - Martin, Charlotte

AU - Tourwe, Dirk

AU - Cavelier, Florine

AU - Gendron, Louis

AU - Sarret, Philippe

AU - Spetea, Mariana

AU - Ballet, Steven

N1 - Funding Information: Drs. M. Bouvier, T. Hebert, S.A. Laporte, G. Pineyro, J.-C. Tardif, and E. Thorin (CQDM Team) are acknowledged for providing us with the Gαq biosensor. This work was supported by the Austrian Research Fund (FWF: I2463-B21 to M.S.), the Research Foundation Flanders (FWO Vlaanderen to S.B.), the Canadian Institutes of Health Research (CIHR) (FDN-148413 to P.S.), and the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2014-06358 to P.S.). P.S. holds a Canada Research Chair in Neurophysiopharmacology of Chronic Pain. E.E. was supported by a doctoral training award from the FRQ-S. M.D. was partly supported by the University of Innsbruck PhD stipend program. Publisher Copyright: © 2020 American Chemical Society. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020/11/12

Y1 - 2020/11/12

N2 - Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the μ-/δ-opioid agonist tetrapeptide H-Dmt-d-Arg-Aba-β-Ala-NH2(KGOP01) was fused to NT(8-13) analogues. Since the NTS1 receptor has been linked to adverse effects, selective MOR-NTS2 ligands are preferred. Modifications were introduced within the native NT sequence, particularly a β3-homo amino acid in position 8 and Tyr11substitutions. Combination of β3hArg and Dmt led to peptide 7, a MOR agonist, showing the highest NTS2 affinity described to date (Ki= 3 pM) and good NTS1 affinity (Ki= 4 nM), providing a >1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue 9 also exhibited high NTS2 affinity (Ki= 1.7 nM), with low NTS1 affinity (Ki= 4.7 μM), resulting in an excellent NTS2 selectivity (>2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.

AB - Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the μ-/δ-opioid agonist tetrapeptide H-Dmt-d-Arg-Aba-β-Ala-NH2(KGOP01) was fused to NT(8-13) analogues. Since the NTS1 receptor has been linked to adverse effects, selective MOR-NTS2 ligands are preferred. Modifications were introduced within the native NT sequence, particularly a β3-homo amino acid in position 8 and Tyr11substitutions. Combination of β3hArg and Dmt led to peptide 7, a MOR agonist, showing the highest NTS2 affinity described to date (Ki= 3 pM) and good NTS1 affinity (Ki= 4 nM), providing a >1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue 9 also exhibited high NTS2 affinity (Ki= 1.7 nM), with low NTS1 affinity (Ki= 4.7 μM), resulting in an excellent NTS2 selectivity (>2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.

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U2 - 10.1021/acs.jmedchem.0c01376

DO - 10.1021/acs.jmedchem.0c01376

M3 - Article

SN - 0022-2623

VL - 63

SP - 12929

EP - 12941

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

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ER -

Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure-Activity Relationship Studies

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