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Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores
Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist,...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775902/ https://www.ncbi.nlm.nih.gov/pubmed/35054860 http://dx.doi.org/10.3390/ijms23020674 |
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author | Witkowska, Ewa Godlewska, Magda Osiejuk, Jowita Gątarz, Sandra Wileńska, Beata Kosińska, Katarzyna Starnowska-Sokół, Joanna Piotrowska, Anna Lipiński, Piotr F. J. Matalińska, Joanna Dyniewicz, Jolanta Halik, Paweł K. Gniazdowska, Ewa Przewlocka, Barbara Misicka, Aleksandra |
author_facet | Witkowska, Ewa Godlewska, Magda Osiejuk, Jowita Gątarz, Sandra Wileńska, Beata Kosińska, Katarzyna Starnowska-Sokół, Joanna Piotrowska, Anna Lipiński, Piotr F. J. Matalińska, Joanna Dyniewicz, Jolanta Halik, Paweł K. Gniazdowska, Ewa Przewlocka, Barbara Misicka, Aleksandra |
author_sort | Witkowska, Ewa |
collection | PubMed |
description | Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors. |
format | Online Article Text |
id | pubmed-8775902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87759022022-01-21 Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores Witkowska, Ewa Godlewska, Magda Osiejuk, Jowita Gątarz, Sandra Wileńska, Beata Kosińska, Katarzyna Starnowska-Sokół, Joanna Piotrowska, Anna Lipiński, Piotr F. J. Matalińska, Joanna Dyniewicz, Jolanta Halik, Paweł K. Gniazdowska, Ewa Przewlocka, Barbara Misicka, Aleksandra Int J Mol Sci Article Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors. MDPI 2022-01-08 /pmc/articles/PMC8775902/ /pubmed/35054860 http://dx.doi.org/10.3390/ijms23020674 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Witkowska, Ewa Godlewska, Magda Osiejuk, Jowita Gątarz, Sandra Wileńska, Beata Kosińska, Katarzyna Starnowska-Sokół, Joanna Piotrowska, Anna Lipiński, Piotr F. J. Matalińska, Joanna Dyniewicz, Jolanta Halik, Paweł K. Gniazdowska, Ewa Przewlocka, Barbara Misicka, Aleksandra Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores |
title | Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores |
title_full | Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores |
title_fullStr | Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores |
title_full_unstemmed | Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores |
title_short | Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores |
title_sort | bifunctional opioid/melanocortin peptidomimetics for use in neuropathic pain: variation in the type and length of the linker connecting the two pharmacophores |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775902/ https://www.ncbi.nlm.nih.gov/pubmed/35054860 http://dx.doi.org/10.3390/ijms23020674 |
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