Journal article 78 views
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 
,
John Martin Corkery,
Giovanni Martinotti,
Stefano L. Sensi ,
Fabrizio Schifano
,
John Martin Corkery,
Giovanni Martinotti,
Stefano L. Sensi ,
Fabrizio Schifano
Frontiers in Chemical Biology
Swansea University Author:
Amira Guirguis
Full text not available from this repository: check for access using links below.
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...
| Published in: | Frontiers in Chemical Biology |
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| ISSN: | 2813-530X |
| Published: |
Frontiers Media SA
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| Online Access: |
Check full text
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| 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. |
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| Keywords: |
ADME, Computational approaches, drug misuse, Drug Overdose, In silico studies, Tolazoline, Xylazine |
| College: |
Faculty of Medicine, Health and Life Sciences |