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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 interactions with human neuroreceptors, specifically the serotonin 7 (5‐HT 7 R) 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‐HT 7 R 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‐HT 7 R 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.
Floresta et al. (Sat,) studied this question.