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

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.