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Despite its increasing prevalence, little is known about its molecular interactions with human neuroreceptors, specifically the serotonin 7 (5\u2010HT<jats:sub>7<\/jats:sub>R) and kappa\u2010opioid (KOR) receptors, which play critical roles in mood regulation, consciousness and nociception. Hence, the binding affinity and molecular interactions of xylazine with both 5\u2010HT<jats:sub>7<\/jats:sub>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\u2010HT<jats:sub>7<\/jats:sub>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\u2010related overdoses.<\/jats:p>","DOI":"10.1002\/ardp.202500041","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T07:42:11Z","timestamp":1742197331000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Xylazine as an emerging new psychoactive substance; focuses on both 5\u2010HT<sub>7<\/sub> and \u03ba\u2010opioid receptors' molecular interactions and isosteric replacement"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0668-1260","authenticated-orcid":false,"given":"Giuseppe","family":"Floresta","sequence":"first","affiliation":[{"name":"Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Health, Medicine and Life 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