In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:94 |
|---|---|
| Enthalten in: |
Archives of toxicology - 94(2020), 11 vom: 08. Nov., Seite 3819-3830 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Vandeputte, Marthe M [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 06.08.2021 Date Revised 24.01.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s00204-020-02855-7 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM313098239 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM313098239 | ||
| 003 | DE-627 | ||
| 005 | 20231225145833.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s00204-020-02855-7 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1043.xml |
| 035 | |a (DE-627)NLM313098239 | ||
| 035 | |a (NLM)32734307 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Vandeputte, Marthe M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 06.08.2021 | ||
| 500 | |a Date Revised 24.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Bio-assay | |
| 650 | 4 | |a Characterization | |
| 650 | 4 | |a New psychoactive substances (NPS) | |
| 650 | 4 | |a Non-fentanyl opioids | |
| 650 | 4 | |a Synthetic opioids | |
| 650 | 4 | |a µ-Opioid receptor | |
| 650 | 7 | |a Analgesics, Opioid |2 NLM | |
| 650 | 7 | |a Illicit Drugs |2 NLM | |
| 650 | 7 | |a Receptors, Opioid, mu |2 NLM | |
| 650 | 7 | |a beta-Arrestin 2 |2 NLM | |
| 650 | 7 | |a GTP-Binding Proteins |2 NLM | |
| 650 | 7 | |a EC 3.6.1.- |2 NLM | |
| 650 | 7 | |a Fentanyl |2 NLM | |
| 650 | 7 | |a UF599785JZ |2 NLM | |
| 700 | 1 | |a Cannaert, Annelies |e verfasserin |4 aut | |
| 700 | 1 | |a Stove, Christophe P |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Archives of toxicology |d 1974 |g 94(2020), 11 vom: 08. Nov., Seite 3819-3830 |w (DE-627)NLM000013374 |x 1432-0738 |7 nnns |
| 773 | 1 | 8 | |g volume:94 |g year:2020 |g number:11 |g day:08 |g month:11 |g pages:3819-3830 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s00204-020-02855-7 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 94 |j 2020 |e 11 |b 08 |c 11 |h 3819-3830 | ||