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Tolazoline, an alpha-adrenergic antagonist, may also block xylazine at off-target sites as inferred from molecular docking

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

Frontiers in Chemical Biology, Volume: 5, Start page: 1806456

Swansea University Author: Amira Guirguis Orcid Logo

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DOI (Published version): 10.3389/fchbi.2026.1806456

Abstract

Xylazine, a non-opioid α2-adrenoceptor agonist, is increasingly implicated in misuse and opioid-adulterated overdoses. Tolazoline, a non-selective α-adrenergic antagonist, is widely used in veterinary medicine to reverse xylazine-induced sedation and cardiovascular depression. Here, we combined mole...

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Published in: Frontiers in Chemical Biology
ISSN: 2813-530X
Published: Frontiers Media SA 2026
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URI: https://cronfa.swan.ac.uk/Record/cronfa71774
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Here, we combined molecular docking, molecular dynamics simulations, and in silico ADME (absorption, distribution, metabolism, and excretion)/Tox predictions to elucidate the pharmacological interplay between xylazine and tolazoline. Both compounds displayed comparable binding energies and stable interactions at the serotonin 5-HT7 and &#x3BA;-opioid receptors, supporting a competitive mechanism at shared receptor sites. Comparative in silico ADME profiling revealed that xylazine exhibits high blood&#x2013;brain barrier penetration, extensive plasma protein binding, and rapid clearance, favouring potent but short-lived central nervous system effects. Conversely, tolazoline was predicted to demonstrate high lipo-solubility levels, low protein binding, large unbound fraction, and long half-life, enabling sustained peripheral &#x3B1;-blockade and sufficient central penetration to counteract xylazine&#x2019;s sedative and sympatholytic actions. 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spelling 2026-06-11T14:04:27.6001996 v2 71774 2026-04-21 Tolazoline, an alpha-adrenergic antagonist, may also block xylazine at off-target sites as inferred from molecular docking b49270b9a0d580cf4f31f9a1b6c93f87 0000-0001-8255-0660 Amira Guirguis Amira Guirguis true false 2026-04-21 MEDS Xylazine, a non-opioid α2-adrenoceptor agonist, is increasingly implicated in misuse and opioid-adulterated overdoses. Tolazoline, a non-selective α-adrenergic antagonist, is widely used in veterinary medicine to reverse xylazine-induced sedation and cardiovascular depression. Here, we combined molecular docking, molecular dynamics simulations, and in silico ADME (absorption, distribution, metabolism, and excretion)/Tox predictions to elucidate the pharmacological interplay between xylazine and tolazoline. Both compounds displayed comparable binding energies and stable interactions at the serotonin 5-HT7 and κ-opioid receptors, supporting a competitive mechanism at shared receptor sites. Comparative in silico ADME profiling revealed that xylazine exhibits high blood–brain barrier penetration, extensive plasma protein binding, and rapid clearance, favouring potent but short-lived central nervous system effects. Conversely, tolazoline was predicted to demonstrate high lipo-solubility levels, low protein binding, large unbound fraction, and long half-life, enabling sustained peripheral α-blockade and sufficient central penetration to counteract xylazine’s sedative and sympatholytic actions. These complementary pharmacokinetic and pharmacodynamic features suggest a mechanistic rationale for tolazoline’s clinical efficacy as an antidote. By integrating receptor-level interactions with kinetic and distributional properties, our findings offer novel insights into the reversal of xylazine intoxication and generate testable predictions for transporter-mediated dynamics and PK/PD (Pharmacokinetic/Pharmacodynamic) modeling. Journal Article Frontiers in Chemical Biology 5 1806456 Frontiers Media SA 2813-530X ADME, computational approaches, drug misuse, drug overdose, in silico studies, tolazoline, xylazine 21 5 2026 2026-05-21 10.3389/fchbi.2026.1806456 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee 2026-06-11T14:04:27.6001996 2026-04-21T12:37:56.2103506 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Giuseppe Floresta 1 Vincenzo Patamia 2 Alberto Granzotto 3 Davide Arillotta 4 Gabriele Duccio Papanti 5 Amira Guirguis 0000-0001-8255-0660 6 John M. Corkery 7 Giovanni Martinotti 8 Stefano L. Sensi 9 Fabrizio Schifano 10 71774__36943__81e34942936d43dabdc6832f780fe376.pdf 71774.VOR.pdf 2026-06-11T14:00:31.3501693 Output 3586402 application/pdf Version of Record true © 2026 Floresta, Patamia, Granzotto, Arillotta, Papanti, Guirguis, Corkery, Martinotti, Sensi and Schifano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). true eng https://creativecommons.org/licenses/by/4.0/
title Tolazoline, an alpha-adrenergic antagonist, may also block xylazine at off-target sites as inferred from molecular docking
spellingShingle Tolazoline, an alpha-adrenergic antagonist, may also block xylazine at off-target sites as inferred from molecular docking
Amira Guirguis
title_short Tolazoline, an alpha-adrenergic antagonist, may also block xylazine at off-target sites as inferred from molecular docking
title_full Tolazoline, an alpha-adrenergic antagonist, may also block xylazine at off-target sites as inferred from molecular docking
title_fullStr Tolazoline, an alpha-adrenergic antagonist, may also block xylazine at off-target sites as inferred from molecular docking
title_full_unstemmed Tolazoline, an alpha-adrenergic antagonist, may also block xylazine at off-target sites as inferred from molecular docking
title_sort Tolazoline, an alpha-adrenergic antagonist, may also block xylazine at off-target sites as inferred from molecular docking
author_id_str_mv b49270b9a0d580cf4f31f9a1b6c93f87
author_id_fullname_str_mv b49270b9a0d580cf4f31f9a1b6c93f87_***_Amira Guirguis
author Amira Guirguis
author2 Giuseppe Floresta
Vincenzo Patamia
Alberto Granzotto
Davide Arillotta
Gabriele Duccio Papanti
Amira Guirguis
John M. Corkery
Giovanni Martinotti
Stefano L. Sensi
Fabrizio Schifano
format Journal article
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container_volume 5
container_start_page 1806456
publishDate 2026
institution Swansea University
issn 2813-530X
doi_str_mv 10.3389/fchbi.2026.1806456
publisher Frontiers Media SA
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
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, a non-opioid α2-adrenoceptor agonist, is increasingly implicated in misuse and opioid-adulterated overdoses. Tolazoline, a non-selective α-adrenergic antagonist, is widely used in veterinary medicine to reverse xylazine-induced sedation and cardiovascular depression. Here, we combined molecular docking, molecular dynamics simulations, and in silico ADME (absorption, distribution, metabolism, and excretion)/Tox predictions to elucidate the pharmacological interplay between xylazine and tolazoline. Both compounds displayed comparable binding energies and stable interactions at the serotonin 5-HT7 and κ-opioid receptors, supporting a competitive mechanism at shared receptor sites. Comparative in silico ADME profiling revealed that xylazine exhibits high blood–brain barrier penetration, extensive plasma protein binding, and rapid clearance, favouring potent but short-lived central nervous system effects. Conversely, tolazoline was predicted to demonstrate high lipo-solubility levels, low protein binding, large unbound fraction, and long half-life, enabling sustained peripheral α-blockade and sufficient central penetration to counteract xylazine’s sedative and sympatholytic actions. These complementary pharmacokinetic and pharmacodynamic features suggest a mechanistic rationale for tolazoline’s clinical efficacy as an antidote. By integrating receptor-level interactions with kinetic and distributional properties, our findings offer novel insights into the reversal of xylazine intoxication and generate testable predictions for transporter-mediated dynamics and PK/PD (Pharmacokinetic/Pharmacodynamic) modeling.
published_date 2026-05-21T05:30:21Z
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