Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT7 and κ‐opioid receptors' molecular interactions and isosteric replacement

Xylazine, traditionally used as a veterinary sedative, has recently emerged as a newpsychoactive substance, being typically ingested in combination with fentanyl de-rivatives and hence raising significant public health concerns. Despite its increasingprevalence, little is known about its molecular interactions with human neuror-eceptors, specifically the serotonin 7 (5‐HT 7R) 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 7R andKOR through docking simulations and molecular dynamics calculations wereinvestigated. These computational approaches revealed critical insights into receptorbinding motifs and highlighted structural modifications that could enhance receptoraffinity. The isosteric replacements within the xylazine structure to improve itsbinding efficacy were assessed, demonstrating that minimal structural modificationscan potentiate its interaction with 5‐HT 7R and KOR. These findings may welladvance our understanding of xylazine's mechanism of action, possibly contributingto identifying suitable treatment/management approaches in treating xylazine‐related overdoses.