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In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances

Marthe Vandeputte (UGent) , Annelies Cannaert (UGent) and Christophe Stove (UGent)
(2020) ARCHIVES OF TOXICOLOGY. 94(11). p.3819-3830
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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, whichmay 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 profles 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 efcacy (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 signifcantly biased. Taken together, this study is the frst 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, 1-SUBSTITUTED 4-(1, 2-DIPHENYLETHYL)PIPERAZINE DERIVATIVES, DRUG, PHARMACOLOGY, MITRAGYNINE, ALKALOIDS, EFFICACY, AGONIST

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Citation

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MLA
Vandeputte, Marthe, et al. “In Vitro Functional Characterization of a Panel of Non-Fentanyl Opioid New Psychoactive Substances.” ARCHIVES OF TOXICOLOGY, vol. 94, no. 11, 2020, pp. 3819–30, doi:10.1007/s00204-020-02855-7.
APA
Vandeputte, M., Cannaert, A., & Stove, C. (2020). In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances. ARCHIVES OF TOXICOLOGY, 94(11), 3819–3830. https://doi.org/10.1007/s00204-020-02855-7
Chicago author-date
Vandeputte, Marthe, Annelies Cannaert, and Christophe Stove. 2020. “In Vitro Functional Characterization of a Panel of Non-Fentanyl Opioid New Psychoactive Substances.” ARCHIVES OF TOXICOLOGY 94 (11): 3819–30. https://doi.org/10.1007/s00204-020-02855-7.
Chicago author-date (all authors)
Vandeputte, Marthe, Annelies Cannaert, and Christophe Stove. 2020. “In Vitro Functional Characterization of a Panel of Non-Fentanyl Opioid New Psychoactive Substances.” ARCHIVES OF TOXICOLOGY 94 (11): 3819–3830. doi:10.1007/s00204-020-02855-7.
Vancouver
1.
Vandeputte M, Cannaert A, Stove C. In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances. ARCHIVES OF TOXICOLOGY. 2020;94(11):3819–30.
IEEE
[1]
M. Vandeputte, A. Cannaert, and C. Stove, “In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances,” ARCHIVES OF TOXICOLOGY, vol. 94, no. 11, pp. 3819–3830, 2020.
@article{8687070,
  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, whichmay 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 profles 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 efcacy (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 signifcantly biased. Taken together, this study is the frst 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.}},
  author       = {{Vandeputte, Marthe and Cannaert, Annelies and Stove, Christophe}},
  issn         = {{0340-5761}},
  journal      = {{ARCHIVES OF TOXICOLOGY}},
  keywords     = {{New psychoactive substances (NPS),Synthetic opioids,Non-fentanyl opioids,Characterization,µ-Opioid receptor,Bio-assay,1-SUBSTITUTED 4-(1,2-DIPHENYLETHYL)PIPERAZINE DERIVATIVES,DRUG,PHARMACOLOGY,MITRAGYNINE,ALKALOIDS,EFFICACY,AGONIST}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{3819--3830}},
  title        = {{In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances}},
  url          = {{http://doi.org/10.1007/s00204-020-02855-7}},
  volume       = {{94}},
  year         = {{2020}},
}

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