In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances
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IN VITRO SYSTEMS
In vitro functional characterization of a panel of non‑fentanyl opioid new psychoactive substances Marthe M. Vandeputte1 · Annelies Cannaert1 · Christophe P. Stove1 Received: 23 April 2020 / Accepted: 14 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The landscape of new psychoactive substances (NPS) is constantly evolving, with new compounds entering the illicit drug market at a continuous pace. Of these, opioid NPS form a threat given their high potency and prevalence. Whereas previously, the use of fentanyl and fentanyl derivatives was the main point of attention, legislations have reacted accordingly, which may have been a driving force towards the (ab)use of alternative µ-opioid receptor (MOR) agonists. In contrast to fentanyl (analogues), details on these novel non-fentanyl opioid NPS are scarce. We investigated the biological activity of a panel of 11 ‘alternative’, newly emerging MOR agonists (2-methyl-AP-237, AP-237, bromadol, brorphine, butorphanol, isotonitazene, mitragynine, 7-OH-mitragynine, MT-45, piperidylthiambutene, and tianeptine) using two closely related in vitro MOR activation bio-assays, monitoring either G protein (mini-Gi), or β-arrestin2 (βarr2) recruitment. Activity profiles were obtained for all tested compounds, with values for potency ( EC50) ranging from 1.89 nM (bromadol) to > 3 µM (AP-237 and tianeptine). Bromadol, brorphine, isotonitazene, piperidylthiambutene, and tianeptine had the highest efficacy (Emax) values, exceeding that of the reference compound hydromorphone ≥ 1.3-fold (βarr2 assay) and > 2.6-fold (mini-Gi assay). Information on the recruitment of two distinct signaling molecules additionally enabled evaluation of biased agonism; none of the evaluated opioids being significantly biased. Taken together, this study is the first to systematically investigate the in vitro biological activity of a diverse panel of emerging non-fentanyl opioid NPS at MOR. Given the known danger of (fatal) intoxications with many opioid NPS, it is important to continuously monitor and characterize newly emerging compounds. Keywords New psychoactive substances (NPS) · Synthetic opioids · Non-fentanyl opioids · Characterization · µ-Opioid receptor · Bio-assay
Introduction The last decade has seen a dynamic growth in the availability and use of new psychoactive substances (NPS) across the globe. By definition not controlled by the United Nations international drug control conventions of 1961 and 1971 (UNODC 2020), these newly misused substances comprise a wide variety of drugs, including synthetic cannabinoid receptor agonists, stimulants, and opioids. NPS are typically labeled as “legal highs”, “research chemicals”, and “not for human consumption”, promoting their allegedly legal status as easily available alternatives for the traditional drugs of * Christophe P. Stove [email protected] 1
Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
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