Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - Neurokinin-1 antagonist peptidomimetics

Karel Guillemyn; Patrycia Kleczkowska; Anna Lesniak; Jolanta Dyniewicz; Olivier Van Der Poorten; Isabelle Van Den Eynde; Attila Keresztes; Eva Varga; Josephine Lai; Frank Porreca; Nga N. Chung; Carole Lemieux; Joanna Mika; Ewelina Rojewska; Wioletta Makuch; Joost Van Duppen; Barbara Przewlocka; Jozef Vanden Broeck; Andrzej W. Lipkowski; Peter W. Schiller; Dirk Tourwé; Steven Ballet

doi:10.1016/j.ejmech.2014.12.033

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - Neurokinin-1 antagonist peptidomimetics

Karel Guillemyn, Patrycia Kleczkowska, Anna Lesniak, Jolanta Dyniewicz, Olivier Van Der Poorten, Isabelle Van Den Eynde, Attila Keresztes, Eva Varga, Josephine Lai, Frank Porreca, Nga N. Chung, Carole Lemieux, Joanna Mika, Ewelina Rojewska, Wioletta Makuch, Joost Van Duppen, Barbara Przewlocka, Jozef Vanden Broeck, Andrzej W. Lipkowski, Peter W. SchillerDirk Tourwé, Steven Ballet

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3′,5′-(CF₃)₂)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat.

Original language	English (US)
Pages (from-to)	64-77
Number of pages	14
Journal	European journal of medicinal chemistry
Volume	92
DOIs	https://doi.org/10.1016/j.ejmech.2014.12.033
State	Published - Dec 25 2015

Keywords

Acute pain
Hybrid peptides
NK1R antagonism
Neuropathic pain
Opioid agonism
Tolerance

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2014.12.033

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Guillemyn, K., Kleczkowska, P., Lesniak, A., Dyniewicz, J., Van Der Poorten, O., Van Den Eynde, I., Keresztes, A., Varga, E., Lai, J., Porreca, F., Chung, N. N., Lemieux, C., Mika, J., Rojewska, E., Makuch, W., Van Duppen, J., Przewlocka, B., Vanden Broeck, J., Lipkowski, A. W., ... Ballet, S. (2015). Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - Neurokinin-1 antagonist peptidomimetics. European journal of medicinal chemistry, 92, 64-77. https://doi.org/10.1016/j.ejmech.2014.12.033

Guillemyn, K, Kleczkowska, P, Lesniak, A, Dyniewicz, J, Van Der Poorten, O, Van Den Eynde, I, Keresztes, A, Varga, E, Lai, J, Porreca, F, Chung, NN, Lemieux, C, Mika, J, Rojewska, E, Makuch, W, Van Duppen, J, Przewlocka, B, Vanden Broeck, J, Lipkowski, AW, Schiller, PW, Tourwé, D & Ballet, S 2015, 'Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - Neurokinin-1 antagonist peptidomimetics', European journal of medicinal chemistry, vol. 92, pp. 64-77. https://doi.org/10.1016/j.ejmech.2014.12.033

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title = "Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - Neurokinin-1 antagonist peptidomimetics",

abstract = "A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3′,5′-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat.",

keywords = "Acute pain, Hybrid peptides, NK1R antagonism, Neuropathic pain, Opioid agonism, Tolerance",

author = "Karel Guillemyn and Patrycia Kleczkowska and Anna Lesniak and Jolanta Dyniewicz and {Van Der Poorten}, Olivier and {Van Den Eynde}, Isabelle and Attila Keresztes and Eva Varga and Josephine Lai and Frank Porreca and Chung, {Nga N.} and Carole Lemieux and Joanna Mika and Ewelina Rojewska and Wioletta Makuch and {Van Duppen}, Joost and Barbara Przewlocka and {Vanden Broeck}, Jozef and Lipkowski, {Andrzej W.} and Schiller, {Peter W.} and Dirk Tourw{\'e} and Steven Ballet",

note = "Publisher Copyright: {\textcopyright} 2014 Published by Elsevier Masson SAS.",

year = "2015",

month = dec,

day = "25",

doi = "10.1016/j.ejmech.2014.12.033",

language = "English (US)",

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pages = "64--77",

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T1 - Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - Neurokinin-1 antagonist peptidomimetics

AU - Guillemyn, Karel

AU - Kleczkowska, Patrycia

AU - Lesniak, Anna

AU - Dyniewicz, Jolanta

AU - Van Der Poorten, Olivier

AU - Van Den Eynde, Isabelle

AU - Keresztes, Attila

AU - Varga, Eva

AU - Lai, Josephine

AU - Porreca, Frank

AU - Chung, Nga N.

AU - Lemieux, Carole

AU - Mika, Joanna

AU - Rojewska, Ewelina

AU - Makuch, Wioletta

AU - Van Duppen, Joost

AU - Przewlocka, Barbara

AU - Vanden Broeck, Jozef

AU - Lipkowski, Andrzej W.

AU - Schiller, Peter W.

AU - Tourwé, Dirk

AU - Ballet, Steven

PY - 2015/12/25

Y1 - 2015/12/25

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AB - A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3′,5′-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat.

KW - Acute pain

KW - Hybrid peptides

KW - NK1R antagonism

KW - Neuropathic pain

KW - Opioid agonism

KW - Tolerance

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JO - European journal of medicinal chemistry

JF - European journal of medicinal chemistry

ER -

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - Neurokinin-1 antagonist peptidomimetics

Abstract

Keywords

ASJC Scopus subject areas

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