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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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    © 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).

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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
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa71774
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 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.
Keywords: ADME, computational approaches, drug misuse, drug overdose, in silico studies, tolazoline, xylazine
College: Faculty of Medicine, Health and Life Sciences
Start Page: 1806456

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