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Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT<sub>7</sub> and κ‐opioid receptors' molecular interactions and isosteric replacement

Giuseppe Floresta Orcid Logo, Alberto Granzotto Orcid Logo, Vincenzo Patamia, Davide Arillotta, Gabriele D. Papanti, Amira Guirguis Orcid Logo, John M. Corkery, Giovanni Martinotti, Stefano L. Sensi, Fabrizio Schifano

Archiv der Pharmazie, Volume: 358, Issue: 3

Swansea University Author: Amira Guirguis Orcid Logo

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DOI (Published version): 10.1002/ardp.202500041

Abstract

Xylazine, traditionally used as a veterinary sedative, has recently emerged as a new psychoactive substance, being typically ingested in combination with fentanyl derivatives and hence raising significant public health concerns. Despite its increasing prevalence, little is known about its molecular...

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Published in: Archiv der Pharmazie
ISSN: 0365-6233 1521-4184
Published: Wiley 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa69109
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spelling 2025-04-10T13:38:15.5114843 v2 69109 2025-03-17 Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT<sub>7</sub> and κ‐opioid receptors' molecular interactions and isosteric replacement b49270b9a0d580cf4f31f9a1b6c93f87 0000-0001-8255-0660 Amira Guirguis Amira Guirguis true false 2025-03-17 MEDS Xylazine, traditionally used as a veterinary sedative, has recently emerged as a new psychoactive substance, being typically ingested in combination with fentanyl derivatives and hence raising significant public health concerns. Despite its increasing prevalence, little is known about its molecular interactions with human neuroreceptors, specifically the serotonin 7 (5-HT7R) and kappa-opioid (KOR) receptors, which play critical roles in mood regulation, consciousness and nociception. Hence, the binding affinity and molecular interactions of xylazine with both 5-HT7R and KOR through docking simulations and molecular dynamics calculations were investigated. These computational approaches revealed critical insights into receptor binding motifs and highlighted structural modifications that could enhance receptor affinity. The isosteric replacements within the xylazine structure to improve its binding efficacy were assessed, demonstrating that minimal structural modifications can potentiate its interaction with 5-HT7R and KOR. These findings may well advance our understanding of xylazine's mechanism of action, possibly contributing to identifying suitable treatment/management approaches in treating xylazine-related overdoses. Journal Article Archiv der Pharmazie 358 3 Wiley 0365-6233 1521-4184 computational approaches, drug misuse, drug overdose, fentanyl, in silico studies 17 3 2025 2025-03-17 10.1002/ardp.202500041 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee 2025-04-10T13:38:15.5114843 2025-03-17T09:57:50.8934508 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Giuseppe Floresta 0000-0002-0668-1260 1 Alberto Granzotto 0000-0001-9181-4373 2 Vincenzo Patamia 3 Davide Arillotta 4 Gabriele D. Papanti 5 Amira Guirguis 0000-0001-8255-0660 6 John M. Corkery 7 Giovanni Martinotti 8 Stefano L. Sensi 9 Fabrizio Schifano 10 69109__33995__2335d29ea23044b599cfc5c0296dcf61.pdf 69109.VoR.pdf 2025-04-10T13:35:37.9992057 Output 3004205 application/pdf Version of Record true © 2025 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License. true eng http://creativecommons.org/licenses/by/4.0/
title Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT<sub>7</sub> and κ‐opioid receptors' molecular interactions and isosteric replacement
spellingShingle Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT<sub>7</sub> and κ‐opioid receptors' molecular interactions and isosteric replacement
Amira Guirguis
title_short Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT<sub>7</sub> and κ‐opioid receptors' molecular interactions and isosteric replacement
title_full Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT<sub>7</sub> and κ‐opioid receptors' molecular interactions and isosteric replacement
title_fullStr Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT<sub>7</sub> and κ‐opioid receptors' molecular interactions and isosteric replacement
title_full_unstemmed Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT<sub>7</sub> and κ‐opioid receptors' molecular interactions and isosteric replacement
title_sort Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT<sub>7</sub> and κ‐opioid receptors' molecular interactions and isosteric replacement
author_id_str_mv b49270b9a0d580cf4f31f9a1b6c93f87
author_id_fullname_str_mv b49270b9a0d580cf4f31f9a1b6c93f87_***_Amira Guirguis
author Amira Guirguis
author2 Giuseppe Floresta
Alberto Granzotto
Vincenzo Patamia
Davide Arillotta
Gabriele D. Papanti
Amira Guirguis
John M. Corkery
Giovanni Martinotti
Stefano L. Sensi
Fabrizio Schifano
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container_title Archiv der Pharmazie
container_volume 358
container_issue 3
publishDate 2025
institution Swansea University
issn 0365-6233
1521-4184
doi_str_mv 10.1002/ardp.202500041
publisher Wiley
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Pharmacy{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Pharmacy
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description Xylazine, traditionally used as a veterinary sedative, has recently emerged as a new psychoactive substance, being typically ingested in combination with fentanyl derivatives and hence raising significant public health concerns. Despite its increasing prevalence, little is known about its molecular interactions with human neuroreceptors, specifically the serotonin 7 (5-HT7R) and kappa-opioid (KOR) receptors, which play critical roles in mood regulation, consciousness and nociception. Hence, the binding affinity and molecular interactions of xylazine with both 5-HT7R and KOR through docking simulations and molecular dynamics calculations were investigated. These computational approaches revealed critical insights into receptor binding motifs and highlighted structural modifications that could enhance receptor affinity. The isosteric replacements within the xylazine structure to improve its binding efficacy were assessed, demonstrating that minimal structural modifications can potentiate its interaction with 5-HT7R and KOR. These findings may well advance our understanding of xylazine's mechanism of action, possibly contributing to identifying suitable treatment/management approaches in treating xylazine-related overdoses.
published_date 2025-03-17T06:22:33Z
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