Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization.

Autor: Vandeputte MM; Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium., Bilel S; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy., Tirri M; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy., Corli G; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy., Bassi M; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy., Layle NK; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, 48108, USA., Fantinati A; Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy., Walther D; Designer Drug Research Unit (DDRU), Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA., Iula DM; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, 48108, USA., Baumann MH; Designer Drug Research Unit (DDRU), Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA., Stove CP; Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium. Electronic address: christophe.stove@ugent.be., Marti M; Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy; Collaborative Center of the National Early Warning System, Department for Anti-Drug Policies, Presidency of the Council of Ministers, Italy. Electronic address: matteo.marti@unife.it.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2024 Dec 01; Vol. 260, pp. 110113. Date of Electronic Publication: 2024 Aug 21.
DOI: 10.1016/j.neuropharm.2024.110113
Abstrakt: The emergence of new synthetic opioids (NSOs) has added complexity to recreational opioid markets worldwide. While NSOs with diverse chemical structures have emerged, brorphine currently remains the only NSO with a piperidine benzimidazolone scaffold. However, the emergence of new generations of NSOs, including brorphine analogues, can be anticipated. This study explored the pharmaco-toxicological, opioid-like effect profile of brorphine alongside its non-brominated analogue (orphine) and three other halogenated analogues (fluorphine, chlorphine, iodorphine). In vitro, radioligand binding assays in rat brain tissue indicated that all analogues bind to the μ-opioid receptor (MOR) with nM affinity. While analogues with smaller-sized substituents showed the highest MOR affinity, further in vitro characterization via two cell-based (HEK 293T) MOR activation (β-arrestin 2 and mini-G αi recruitment) assays indicated that chlorphine, brorphine, and iodorphine were generally the most active MOR agonists. None of the compounds showed significant in vitro biased agonism compared to hydromorphone. In vivo, we investigated the effects of intraperitoneal (IP) administration of the benzimidazolones (0.01-15 mg/kg) on mechanical and thermal antinociception in male CD-1 mice. Chlorphine and brorphine overall induced the highest levels of antinociception. Furthermore, the effects on respiratory changes induced by a fixed dose (15 mg/kg IP) of the compounds were investigated using non-invasive plethysmography. Fluorphine-, chlorphine-, and brorphine-induced respiratory depressant effects were the most pronounced. For some compounds, pretreatment with naloxone (6 mg/kg IP) could not reverse respiratory depression. Taken together, brorphine-like piperidine benzimidazolones are opioid agonists that have the potential to cause substantial harm to users should they emerge as NSOs. This article is part of the Special Issue on "Novel Synthetic Opioids (NSOs)".
Competing Interests: Declaration of competing interest The authors have nothing to disclose.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: