Pharmacological characterization of novel synthetic opioids: Isotonitazene, metonitazene, and piperidylthiambutene as potent μ-opioid receptor agonists

De Luca, Maria Antonietta, Tocco, Graziella, Ucha, Marcos y et al. . (2022) Pharmacological characterization of novel synthetic opioids: Isotonitazene, metonitazene, and piperidylthiambutene as potent μ-opioid receptor agonists. Neuropharmacology 221 (2022) 109263

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Título Pharmacological characterization of novel synthetic opioids: Isotonitazene, metonitazene, and piperidylthiambutene as potent μ-opioid receptor agonists
Autor(es) De Luca, Maria Antonietta
Tocco, Graziella
Ucha, Marcos
et al.
Materia(s) Psicología
Abstract Recent trends of opioid abuse and related fatalities have highlighted the critical role of Novel Synthetic Opioids (NSOs). We studied the μ-opioid-like properties of isotonitazene (ITZ), metonitazene (MTZ), and piperidylthiambutene (PTB) using different approaches. In vitro studies showed that ITZ and MTZ displayed a higher potency in both rat membrane homogenates (EC50:0.99 and 19.1 nM, respectively) and CHO-MOR (EC50:0.71 and 10.0 nM, respectively) than [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO), with no difference in maximal efficacy (Emax) between DAMGO and NSOs. ITZ also has higher affinity (Ki:0.06 and 0.05 nM) at the MOR than DAMGO in both systems, whilst MTZ has higher affinity in CHO-MOR (Ki=0.23 nM) and similar affinity in rat cerebral cortex (Ki = 0.22 nM). PTB showed lower affinity and potency than DAMGO. In vivo, ITZ displayed higher analgesic potency than fentanyl and morphine (ED50:0.00156, 0.00578, 2.35 mg/kg iv, respectively); ITZ (0.01 mg/kg iv) and MTZ (0.03 mg/kg iv) reduced behavioral activity and increased dialysate dopamine (DA) in the NAc shell (max. about 200% and 170% over basal value, respectively. Notably, ITZ elicited an increase in DA comparable to that of higher dose of morphine (1 mg/kg iv), but higher than the same dose of fentanyl (0.01 mg/ kg iv). In silico, induced fit docking (IFD) and metadynamic simulations (MTD) showed that binding modes and structural changes at the receptor, ligand stability, and the overall energy score of NSOs were consistent with the results of the biological assays.
Palabras clave GTPγS binding
MOR binding
In silico studies
Dopamine
Nitazenes
Nociception
Microdialysis
Editor(es) Elsevier
Fecha 2022
Formato application/pdf
Identificador bibliuned:DptoPSIBIO-FPSI-Articulos-Mucha-0006
http://e-spacio.uned.es/fez/view/bibliuned:DptoPSIBIO-FPSI-Articulos-Mucha-0006
DOI - identifier https://doi.org/10.1016/j.neuropharm.2022.109263
ISSN - identifier 0028-3908
Nombre de la revista Neuropharmacology
Número de Volumen 221
Publicado en la Revista Neuropharmacology 221 (2022) 109263
Idioma eng
Versión de la publicación publishedVersion
Tipo de recurso Article
Derechos de acceso y licencia http://creativecommons.org/licenses/by-nc-nd/4.0
info:eu-repo/semantics/openAccess
Tipo de acceso Acceso abierto
Notas adicionales The registered version of this article, first published in Neuropharmacology, is available online at the publisher's website: Elsevier, https://doi.org/10.1016/j.neuropharm.2022.109263
Notas adicionales La versión registrada de este artículo, publicado por primera vez en Neuropharmacology, está disponible en línea en el sitio web del editor: Elsevier, https://doi.org/10.1016/j.neuropharm.2022.109263

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Creado: Wed, 31 Jan 2024, 22:49:56 CET