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Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl

Cyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities (K(a) ~ 100–200 M(-1)) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their...

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Autores principales: Mayer, Brian P., Kennedy, Daniel J., Lau, Edmond Y., Valdez, Carlos A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932099/
https://www.ncbi.nlm.nih.gov/pubmed/36792632
http://dx.doi.org/10.1038/s41598-023-29662-1
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author Mayer, Brian P.
Kennedy, Daniel J.
Lau, Edmond Y.
Valdez, Carlos A.
author_facet Mayer, Brian P.
Kennedy, Daniel J.
Lau, Edmond Y.
Valdez, Carlos A.
author_sort Mayer, Brian P.
collection PubMed
description Cyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities (K(a) ~ 100–200 M(-1)) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their binding affinity towards fentanyl hydrochloride. The optimal CD studied displays a remarkable affinity for the opioid of K(a) = 66,500 M(−1), the largest value reported for such an inclusion complex to date. One dimensional (1)H Nuclear Magnetic Resonance (NMR) as well as Rotational Frame Overhauser Spectroscopy (2D-ROESY) experiments supported by molecular dynamics (MD) simulations suggest an unexpected binding behavior, with fentanyl able to bind the CD interior in one of two distinct orientations. Binding energies derived from the MD simulations work correlate strongly with NMR-derived affinities highlighting its utility as a predictive tool for CD candidate optimization. The performance of these host molecules portends their utility as platforms for medical countermeasures for opioid exposure, as biosensors, and in other forensic science applications.
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spelling pubmed-99320992023-02-17 Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl Mayer, Brian P. Kennedy, Daniel J. Lau, Edmond Y. Valdez, Carlos A. Sci Rep Article Cyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities (K(a) ~ 100–200 M(-1)) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their binding affinity towards fentanyl hydrochloride. The optimal CD studied displays a remarkable affinity for the opioid of K(a) = 66,500 M(−1), the largest value reported for such an inclusion complex to date. One dimensional (1)H Nuclear Magnetic Resonance (NMR) as well as Rotational Frame Overhauser Spectroscopy (2D-ROESY) experiments supported by molecular dynamics (MD) simulations suggest an unexpected binding behavior, with fentanyl able to bind the CD interior in one of two distinct orientations. Binding energies derived from the MD simulations work correlate strongly with NMR-derived affinities highlighting its utility as a predictive tool for CD candidate optimization. The performance of these host molecules portends their utility as platforms for medical countermeasures for opioid exposure, as biosensors, and in other forensic science applications. Nature Publishing Group UK 2023-02-15 /pmc/articles/PMC9932099/ /pubmed/36792632 http://dx.doi.org/10.1038/s41598-023-29662-1 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Mayer, Brian P.
Kennedy, Daniel J.
Lau, Edmond Y.
Valdez, Carlos A.
Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
title Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
title_full Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
title_fullStr Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
title_full_unstemmed Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
title_short Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
title_sort evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932099/
https://www.ncbi.nlm.nih.gov/pubmed/36792632
http://dx.doi.org/10.1038/s41598-023-29662-1
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