{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T03:07:27Z","timestamp":1793070447453,"version":"4.5.0"},"reference-count":82,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:00:00Z","timestamp":1718323200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:00:00Z","timestamp":1718323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100007236","name":"Office of Justice Programs","doi-asserted-by":"publisher","award":["15PNIJ-22-GG-04434-MUMU"],"award-info":[{"award-number":["15PNIJ-22-GG-04434-MUMU"]}],"id":[{"id":"10.13039\/100007236","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["11I5623N"],"award-info":[{"award-number":["11I5623N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["1S81522N"],"award-info":[{"award-number":["1S81522N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G069419N"],"award-info":[{"award-number":["G069419N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007229","name":"Bijzonder Onderzoeksfonds UGent","doi-asserted-by":"publisher","award":["BOF23\/PDO\/073"],"award-info":[{"award-number":["BOF23\/PDO\/073"]}],"id":[{"id":"10.13039\/501100007229","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007229","name":"Bijzonder Onderzoeksfonds UGent","doi-asserted-by":"publisher","award":["01J15517"],"award-info":[{"award-number":["01J15517"]}],"id":[{"id":"10.13039\/501100007229","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    2-Benzylbenzimidazole \u2018nitazene\u2019 opioids are presenting a growing threat to public health. Although various nitazenes were previously studied, systematic comparisons of the effects of different structural modifications to the 2-benzylbenzimidazole core structure on \u03bc-opioid receptor (MOR) activity are limited. Here, we assessed in vitro structure\u2013activity relationships of 9 previously uncharacterized nitazenes alongside known structural analogues. Specifically, we focused on MOR activation by \u2018ring\u2019 substituted analogues (i.e.,\n                    <jats:italic>N<\/jats:italic>\n                    -pyrrolidino and\n                    <jats:italic>N<\/jats:italic>\n                    -piperidinyl modifications), \u2018desnitazene\u2019 analogues (lacking the 5-nitro group), and\n                    <jats:italic>N<\/jats:italic>\n                    -desethyl analogues. The results from two in vitro MOR activation assays (\u03b2-arrestin 2 recruitment and inhibition of cAMP accumulation) showed that \u2018ring\u2019 modifications overall yield highly active drugs. With the exception of 4\u2032-OH analogues (which are metabolites),\n                    <jats:italic>N<\/jats:italic>\n                    -pyrrolidino substitutions were generally more favorable for MOR activation than\n                    <jats:italic>N<\/jats:italic>\n                    -piperidine substitutions. Furthermore, removal of the 5-nitro group on the benzimidazole ring consistently caused a pronounced decrease in potency. The\n                    <jats:italic>N<\/jats:italic>\n                    -desethyl modifications showed important MOR activity, and generally resulted in a slightly lowered potency than comparator nitazenes. Intriguingly,\n                    <jats:italic>N<\/jats:italic>\n                    -desethyl isotonitazene was the exception and was consistently more potent than isotonitazene. Complementing the in vitro findings and demonstrating the high harm potential associated with many of these compounds, we describe 85 forensic cases from North America and the United Kingdom involving etodesnitazene,\n                    <jats:italic>N<\/jats:italic>\n                    -desethyl etonitazene,\n                    <jats:italic>N<\/jats:italic>\n                    -desethyl isotonitazene,\n                    <jats:italic>N<\/jats:italic>\n                    -pyrrolidino metonitazene, and\n                    <jats:italic>N<\/jats:italic>\n                    -pyrrolidino protonitazene. The low-to-sub ng\/mL blood concentrations observed in most cases underscore the drugs\u2019 high potencies. Taken together, by bridging pharmacology and case data, this study may aid to increase awareness and guide legislative and public health efforts.\n                  <\/jats:p>","DOI":"10.1007\/s00204-024-03774-7","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T14:02:46Z","timestamp":1718373766000},"page":"2999-3018","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["In vitro structure\u2013activity relationships and forensic case series of emerging 2-benzylbenzimidazole \u2018nitazene\u2019 opioids"],"prefix":"10.1007","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5065-8965","authenticated-orcid":false,"given":"Liam M.","family":"De Vrieze","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Walton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9077-4055","authenticated-orcid":false,"given":"Eline","family":"Pottie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1638-3259","authenticated-orcid":false,"given":"Donna","family":"Papsun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2400-4711","authenticated-orcid":false,"given":"Barry K.","family":"Logan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1775-1882","authenticated-orcid":false,"given":"Alex J.","family":"Krotulski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7126-348X","authenticated-orcid":false,"given":"Christophe P.","family":"Stove","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1431-441X","authenticated-orcid":false,"given":"Marthe M.","family":"Vandeputte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,14]]},"reference":[{"key":"3774_CR1","unstructured":"117th Congress (2021) H.R. 5305\u2014Extending government funding and delivering emergency assistance act"},{"key":"3774_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(19)30218-4","volume":"6","author":"Y Bao","year":"2019","unstructured":"Bao Y, Meng S, Shi J, Lu L (2019) Control of fentanyl-related substances in China. Lancet Psychiatry 6:e15. https:\/\/doi.org\/10.1016\/S2215-0366(19)30218-4","journal-title":"Lancet Psychiatry"},{"key":"3774_CR3","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/j.tips.2018.09.006","volume":"39","author":"MH Baumann","year":"2018","unstructured":"Baumann MH, Kopajtic TA, Madras BK (2018) Pharmacological research as a key component in mitigating the opioid overdose crisis. Trends Pharmacol Sci 39:995\u2013998. https:\/\/doi.org\/10.1016\/j.tips.2018.09.006","journal-title":"Trends Pharmacol Sci"},{"key":"3774_CR4","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2023-1360","author":"D Berardinelli","year":"2024","unstructured":"Berardinelli D, Taoussi O, Carlier J et al (2024) In vitro, in vivo metabolism and quantification of the novel synthetic opioid N-piperidinyl etonitazene (etonitazepipne). Clin Chem Lab Med. https:\/\/doi.org\/10.1515\/cclm-2023-1360","journal-title":"Clin Chem Lab Med"},{"key":"3774_CR5","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1002\/dta.2738","volume":"12","author":"P Blanckaert","year":"2020","unstructured":"Blanckaert P, Cannaert A, Van Uytfanghe K et al (2020) Report on a novel emerging class of highly potent benzimidazole NPS opioids: chemical and in vitro functional characterization of isotonitazene. Drug Test Anal 12:422\u2013430. https:\/\/doi.org\/10.1002\/dta.2738","journal-title":"Drug Test Anal"},{"key":"3774_CR6","first-page":"31","volume":"70","author":"H Brandenberger","year":"1974","unstructured":"Brandenberger H (1974) Rolle des massenspektrometers im toxikologisch-chemischen laboratorium. Dtsch Lebensm-Rundsch 70:31\u201339","journal-title":"Dtsch Lebensm-Rundsch"},{"key":"3774_CR7","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1007\/BF01486702","volume":"36","author":"G Bromig","year":"1958","unstructured":"Bromig G (1958) \u00dcber neue starkwirkende analgetika und ihre klinische erprobung. Klin Wochenschr 36:960\u2013963. https:\/\/doi.org\/10.1007\/BF01486702","journal-title":"Klin Wochenschr"},{"key":"3774_CR8","unstructured":"Burnhill E (2024) Increase in synthetic drugs led to multiple overdoses last year, says HSE. https:\/\/www.rte.ie\/news\/health\/2024\/0104\/1424628-synthetic-drugs\/. Accessed 5 Mar 2024"},{"key":"3774_CR9","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1373\/clinchem.2018.289496","volume":"64","author":"A Cannaert","year":"2018","unstructured":"Cannaert A, Vasudevan L, Friscia M et al (2018) Activity-based concept to screen biological matrices for opiates and (synthetic) opioids. Clin Chem 64:1221\u20131229. https:\/\/doi.org\/10.1373\/clinchem.2018.289496","journal-title":"Clin Chem"},{"key":"3774_CR10","unstructured":"CDC (2023) Drug overdose deaths. https:\/\/www.cdc.gov\/drugoverdose\/deaths\/index.html. Accessed 24 Aug 2023"},{"key":"3774_CR11","unstructured":"CFSRE (2023) NPS discovery. https:\/\/www.cfsre.org\/nps-discovery\/. Accessed 28 Dec 2023"},{"key":"3774_CR12","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.neuropharm.2013.08.028","volume":"76","author":"P Charbogne","year":"2014","unstructured":"Charbogne P, Kieffer BL, Befort K (2014) 15 years of genetic approaches in vivo for addiction research: opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology 76:204\u2013217. https:\/\/doi.org\/10.1016\/j.neuropharm.2013.08.028","journal-title":"Neuropharmacology"},{"key":"3774_CR13","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.3390\/molecules28041601","volume":"28","author":"K Chaturvedi","year":"2023","unstructured":"Chaturvedi K, Hewamanna I, Pandey P et al (2023) Identification of the putative binding site of a benzimidazole opioid (etazene) and its metabolites at \u03bc-opioid receptor: a human liver microsomal assay and systematic computational study. Molecules 28:1601. https:\/\/doi.org\/10.3390\/molecules28041601","journal-title":"Molecules"},{"key":"3774_CR14","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2022.109263","volume":"221","author":"MA De Luca","year":"2022","unstructured":"De Luca MA, Tocco G, Mostallino R et al (2022) Pharmacological characterization of novel synthetic opioids: isotonitazene, metonitazene, and piperidylthiambutene as potent \u03bc-opioid receptor agonists. Neuropharmacology 221:109263. https:\/\/doi.org\/10.1016\/j.neuropharm.2022.109263","journal-title":"Neuropharmacology"},{"key":"3774_CR15","unstructured":"DEA (2021) Schedules of controlled substances: placement of isotonitazene in Schedule I"},{"key":"3774_CR16","unstructured":"DEA (2022) Schedules of controlled substances: temporary placement of butonitazene, etodesnitazene, flunitazene, metodesnitazene, metonitazene, N-pyrrolidino etonitazene, and protonitazene in Schedule I"},{"key":"3774_CR17","unstructured":"DEA (2023) Schedules of controlled substances: temporary placement of N-desethyl isotonitazene and N-piperidinyl etonitazene in Schedule I"},{"key":"#cr-split#-3774_CR18.1","unstructured":"EC (2020) Commission Delegated Directive"},{"key":"#cr-split#-3774_CR18.2","unstructured":"(EU) 2020\/1687 of 2 September 2020 amending the Annex to Council Framework Decision 2004\/757\/JHA as regards the inclusion of the new psychoactive substance N,N-diethyl-2-[[4-(1-methylethoxy)phenyl]methyl]-5-nitro-1H-benzimidazole-1-ethanamine (isotonitazene) in the definition of 'drug'"},{"key":"3774_CR19","volume-title":"Report on the risk assessment of N,N-diethyl-2-[[4-(1-methylethoxy) phenyl] methyl]-5-nitro-1H-benzimidazole-1-ethanamine (isotonitazene) in accordance with Article 5c of Regulation (EC) No 1920\/2006 (as amended)","author":"EMCDDA","year":"2020","unstructured":"EMCDDA (2020) Report on the risk assessment of N,N-diethyl-2-[[4-(1-methylethoxy) phenyl] methyl]-5-nitro-1H-benzimidazole-1-ethanamine (isotonitazene) in accordance with Article 5c of Regulation (EC) No 1920\/2006 (as amended). Publications Office, Luxembourg"},{"key":"3774_CR20","volume-title":"European drug report 2023: trends and developments","author":"EMCDDA","year":"2023","unstructured":"EMCDDA (2023) European drug report 2023: trends and developments. Publications Office of the European Union, Luxembourg"},{"key":"3774_CR80","unstructured":"EMCDDA European Database on New Drugs (EDND) (restricted access). https:\/\/ednd2.emcdda.europa.eu\/ednd\/login. Accessed 15 May 2024"},{"key":"3774_CR21","doi-asserted-by":"publisher","first-page":"S112","DOI":"10.1016\/j.toxac.2022.06.178","volume":"34","author":"M Fogarty","year":"2022","unstructured":"Fogarty M, Walton S, Papsun D et al (2022) A novel approach to verifying and implementing a quantitative standard addition analysis of NPS drugs in forensic toxicology samples. Toxicol Anal Clin 34:S112. https:\/\/doi.org\/10.1016\/j.toxac.2022.06.178","journal-title":"Toxicol Anal Clin"},{"issue":"12","key":"3774_CR22","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1111\/add.16318","volume":"118","author":"J Friedman","year":"2023","unstructured":"Friedman J, Shover CL (2023) Charting the fourth wave: geographic, temporal, race\/ethnicity and demographic trends in polysubstance fentanyl overdose deaths in the United States, 2010\u20132021. Addiction 118(12):2477\u20132485. https:\/\/doi.org\/10.1111\/add.16318","journal-title":"Addiction"},{"key":"3774_CR23","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1093\/jat\/bkw013","volume":"40","author":"D Gerostamoulos","year":"2016","unstructured":"Gerostamoulos D, Elliott S, Walls HC et al (2016) To measure or not to measure? That is the NPS question. J Anal Toxicol 40:318\u2013320. https:\/\/doi.org\/10.1093\/jat\/bkw013","journal-title":"J Anal Toxicol"},{"key":"3774_CR24","doi-asserted-by":"publisher","first-page":"eaaz3140","DOI":"10.1126\/scisignal.aaz3140","volume":"13","author":"A Gillis","year":"2020","unstructured":"Gillis A, Gondin AB, Kliewer A et al (2020) Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci Signal 13:eaaz3140. https:\/\/doi.org\/10.1126\/scisignal.aaz3140","journal-title":"Sci Signal"},{"issue":"4","key":"3774_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(24)00024-0","volume":"9","author":"I Giraudon","year":"2024","unstructured":"Giraudon I, Abel-Ollo K, Vanaga-Ar\u0101ja D et al (2024) Nitazenes represent a growing threat to public health in Europe. Lancet Public Health 9(4):e216. https:\/\/doi.org\/10.1016\/S2468-2667(24)00024-0","journal-title":"Lancet Public Health"},{"issue":"12","key":"3774_CR26","doi-asserted-by":"publisher","first-page":"2573","DOI":"10.1007\/s00213-023-06451-2","volume":"240","author":"GC Glatfelter","year":"2023","unstructured":"Glatfelter GC, Vandeputte MM, Chen L et al (2023) Alkoxy chain length governs the potency of 2-benzylbenzimidazole \u2018nitazene\u2019 opioids associated with human overdose. Psychopharmacology 240(12):2573\u20132584. https:\/\/doi.org\/10.1007\/s00213-023-06451-2","journal-title":"Psychopharmacology"},{"key":"3774_CR27","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1007\/BF02161117","volume":"13","author":"F Gross","year":"1957","unstructured":"Gross F, Turrian H (1957) \u00dcber benzimidazolderivate mit starker analgetischer wirkung. Experientia 13:401\u2013403. https:\/\/doi.org\/10.1007\/BF02161117","journal-title":"Experientia"},{"key":"3774_CR28","doi-asserted-by":"publisher","first-page":"e71","DOI":"10.1016\/S2468-2667(24)00001-X","volume":"9","author":"A Holland","year":"2024","unstructured":"Holland A, Copeland CS, Shorter GW et al (2024) Nitazenes\u2014heralding a second wave for the UK drug-related death crisis? Lancet Public Health 9:e71\u2013e72. https:\/\/doi.org\/10.1016\/S2468-2667(24)00001-X","journal-title":"Lancet Public Health"},{"key":"3774_CR29","unstructured":"HSE (2024) Synthetic opioid preparation. https:\/\/www.drugs.ie\/synthetic_opioid_preparation\/. Accessed 5 Mar 2024"},{"key":"3774_CR30","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1007\/BF02161116","volume":"13","author":"A Hunger","year":"1957","unstructured":"Hunger A, Kebrle J, Rossi A, Hoffmann K (1957) Synthese basisch substituierter, analgetisch wirksamer benzimidazol-derivate. Experientia 13:400\u2013401. https:\/\/doi.org\/10.1007\/BF02161116","journal-title":"Experientia"},{"key":"3774_CR31","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1002\/hlca.19600430323","volume":"43","author":"A Hunger","year":"1960","unstructured":"Hunger A, Kebrle J, Rossi A, Hoffmann K (1960a) Benzimidazol-derivate und verwandte heterocyclen. II. Synthese von 1-aminoalkyl-2-benzyl-benzimidazolen. Helv Chim Acta 43:800\u2013809. https:\/\/doi.org\/10.1002\/hlca.19600430323","journal-title":"Helv Chim Acta"},{"key":"3774_CR32","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1002\/hlca.19600430412","volume":"43","author":"A Hunger","year":"1960","unstructured":"Hunger A, Kebrle J, Rossi A, Hoffmann K (1960b) Benzimidazol-derivate und verwandte heterocyclen III. Synthese von 1-aminoalkyl-2-nenzyl-nitro-benzimidazolen. Helv Chim Acta 43:1032\u20131046. https:\/\/doi.org\/10.1002\/hlca.19600430412","journal-title":"Helv Chim Acta"},{"key":"3774_CR33","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1002\/dta.3415","volume":"15","author":"T Kanamori","year":"2023","unstructured":"Kanamori T, Okada Y, Segawa H et al (2023) Analysis of highly potent synthetic opioid nitazene analogs and their positional isomers. Drug Test Anal 15:449\u2013457. https:\/\/doi.org\/10.1002\/dta.3415","journal-title":"Drug Test Anal"},{"key":"3774_CR78","doi-asserted-by":"publisher","DOI":"10.1002\/dta.3705","author":"T Kanamori","year":"2024","unstructured":"Kanamori T, Okada Y, Segawa H et al (2024) Metabolism of highly potent synthetic opioid nitazene analogs: N-ethyl-N-(1-glucuronyloxyethyl) metabolite formation and degradation to N-desethyl metabolites during enzymatic hydrolysis. Drug Test Anal. https:\/\/doi.org\/10.1002\/dta.3705","journal-title":"Drug Test Anal"},{"key":"3774_CR79","doi-asserted-by":"publisher","DOI":"10.1111\/add.16525","author":"N Killeen","year":"2024","unstructured":"Killeen N, Lakes R, Webster M et al (2024) The emergence of nitazenes on the Irish heroin market and national preparation for possible future outbreaks. Addiction. https:\/\/doi.org\/10.1111\/add.16525","journal-title":"Addiction"},{"key":"3774_CR81","doi-asserted-by":"publisher","DOI":"10.1002\/dta.3707","author":"S Killoran","year":"2024","unstructured":"Killoran S, McNamara S, Kavanagh P et al (2024) Identification of N-pyrrolidino protonitazene in powders sold as heroin and associated with overdose clusters in Dublin and Cork, Ireland. Drug Test Anal. https:\/\/doi.org\/10.1002\/dta.3707","journal-title":"Drug Test Anal"},{"issue":"2","key":"3774_CR34","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1124\/jpet.123.002052","volume":"389","author":"LB Kozell","year":"2024","unstructured":"Kozell LB, Eshleman AJ, Wolfrum KM et al (2024) Pharmacologic characterization of substituted nitazenes at mu, kappa and delta opioid receptors suggests high potential for toxicity. J Pharmacol Exp Ther 389(2):219\u2013228. https:\/\/doi.org\/10.1124\/jpet.123.002052","journal-title":"J Pharmacol Exp Ther"},{"key":"3774_CR35","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1093\/jat\/bkaa016","volume":"44","author":"AJ Krotulski","year":"2020","unstructured":"Krotulski AJ, Papsun DM, Kacinko SL, Logan BK (2020) Isotonitazene quantitation and metabolite discovery in authentic forensic casework. J Anal Toxicol 44:521\u2013530. https:\/\/doi.org\/10.1093\/jat\/bkaa016","journal-title":"J Anal Toxicol"},{"key":"3774_CR36","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1111\/1556-4029.14623","volume":"66","author":"AJ Krotulski","year":"2021","unstructured":"Krotulski AJ, Papsun DM, Noble C et al (2021a) Brorphine\u2014investigation and quantitation of a new potent synthetic opioid in forensic toxicology casework using liquid chromatography-mass spectrometry. J Forensic Sci 66:664\u2013676. https:\/\/doi.org\/10.1111\/1556-4029.14623","journal-title":"J Forensic Sci"},{"key":"3774_CR37","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1002\/dta.3115","volume":"13","author":"AJ Krotulski","year":"2021","unstructured":"Krotulski AJ, Papsun DM, Walton SE, Logan BK (2021b) Metonitazene in the United States\u2014forensic toxicology assessment of a potent new synthetic opioid using liquid chromatography mass spectrometry. Drug Test Anal 13:1697\u20131711. https:\/\/doi.org\/10.1002\/dta.3115","journal-title":"Drug Test Anal"},{"key":"3774_CR38","unstructured":"Krotulski A, Papsun D, Walton SE, Logan BK (2022) Benzo-dope: an increasingly prevalent drug combination of significant toxicological relevance. Society of forensic toxicologist (SOFT)- 2022 conference meeting"},{"key":"3774_CR39","unstructured":"Krotulski AJ, Walton SE, Mohr ALA, Logan BK (2023) Trend report Q3 2023: NPS opioids in the United States. https:\/\/www.cfsre.org\/images\/trendreports\/2023-Q3-NPS-Opioids-Trend-Report.pdf. Accessed 8 May 2024"},{"key":"3774_CR76","unstructured":"Krotulski AJ, Walton SE, Mohr ALA, Logan BK (2024) Trend report Q1 2024: NPS opioids in the United States. https:\/\/www.cfsre.org\/images\/trendreports\/2024-Q1-NPS-Opioids-Trend-Report.pdf. Accessed 8 May 2024"},{"key":"3774_CR41","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugpo.2021.103169","volume":"93","author":"MK Laing","year":"2021","unstructured":"Laing MK, Ti L, Marmel A et al (2021) An outbreak of novel psychoactive substance benzodiazepines in the unregulated drug supply: preliminary results from a community drug checking program using point-of-care and confirmatory methods. Int J Drug Policy 93:103169. https:\/\/doi.org\/10.1016\/j.drugpo.2021.103169","journal-title":"Int J Drug Policy"},{"key":"3774_CR42","doi-asserted-by":"publisher","first-page":"107121","DOI":"10.1016\/j.isci.2023.107121","volume":"26","author":"NJ Malcolm","year":"2023","unstructured":"Malcolm NJ, Palkovic B, Sprague DJ et al (2023) Mu-opioid receptor selective superagonists produce prolonged respiratory depression. iScience 26:107121. https:\/\/doi.org\/10.1016\/j.isci.2023.107121","journal-title":"iScience"},{"key":"3774_CR43","unstructured":"Martin A-C, Cobham T, Thomas R (2023) Is the UK sleepwalking into a lethal US-style opioid drugs crisis? The Independent"},{"key":"3774_CR44","doi-asserted-by":"publisher","first-page":"3033","DOI":"10.1038\/s41467-020-16664-0","volume":"11","author":"M Meyrath","year":"2020","unstructured":"Meyrath M, Szpakowska M, Zeiner J et al (2020) The atypical chemokine receptor ACKR3\/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nat Commun 11:3033. https:\/\/doi.org\/10.1038\/s41467-020-16664-0","journal-title":"Nat Commun"},{"key":"3774_CR45","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1097\/FTD.0000000000000970","volume":"44","author":"E Montanari","year":"2022","unstructured":"Montanari E, Madeo G, Pichini S et al (2022) Acute intoxications and fatalities associated with benzimidazole opioid (nitazene analog) use: a systematic review. Ther Drug Monit 44:494. https:\/\/doi.org\/10.1097\/FTD.0000000000000970","journal-title":"Ther Drug Monit"},{"key":"3774_CR46","unstructured":"Morris H (2009) Synthetic opioids: the most addictive drugs in the world. https:\/\/www.vice.com\/en\/article\/9bdymy\/hamiltonspharmacopeia-804-v16n4. Accessed 27 July 2023"},{"key":"3774_CR47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jat\/bky049","volume":"43","author":"JB Morrow","year":"2019","unstructured":"Morrow JB, Ropero-Miller JD, Catlin ML et al (2019) The opioid epidemic: moving toward an integrated, holistic analytical response. J Anal Toxicol 43:1\u20139. https:\/\/doi.org\/10.1093\/jat\/bky049","journal-title":"J Anal Toxicol"},{"key":"3774_CR48","doi-asserted-by":"publisher","DOI":"10.1016\/j.forsciint.2021.110686","volume":"320","author":"F Mueller","year":"2021","unstructured":"Mueller F, Bogdal C, Pfeiffer B et al (2021) Isotonitazene: fatal intoxication in three cases involving this unreported novel psychoactive substance in Switzerland. Forensic Sci Int 320:110686. https:\/\/doi.org\/10.1016\/j.forsciint.2021.110686","journal-title":"Forensic Sci Int"},{"key":"3774_CR40","unstructured":"NMS Labs (2023) Illicit drugs. https:\/\/www.nmslabs.com\/solutions\/illicit-drugs. Accessed 28 Dec 2023"},{"key":"3774_CR49","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114251","volume":"182","author":"E Pottie","year":"2020","unstructured":"Pottie E, Dedecker P, Stove CP (2020a) Identification of psychedelic new psychoactive substances (NPS) showing biased agonism at the 5-HT2AR through simultaneous use of \u03b2-arrestin 2 and miniG\u03b1q bioassays. Biochem Pharmacol 182:114251. https:\/\/doi.org\/10.1016\/j.bcp.2020.114251","journal-title":"Biochem Pharmacol"},{"key":"3774_CR50","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.113934","volume":"177","author":"E Pottie","year":"2020","unstructured":"Pottie E, Tosh DK, Gao Z-G et al (2020b) Assessment of biased agonism at the A3 adenosine receptor using \u03b2-arrestin and miniG\u03b1i recruitment assays. Biochem Pharmacol 177:113934. https:\/\/doi.org\/10.1016\/j.bcp.2020.113934","journal-title":"Biochem Pharmacol"},{"key":"3774_CR51","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1080\/15563650.2024.2309321","volume":"62","author":"M Pucci","year":"2024","unstructured":"Pucci M, Singh Jutley G, Looms J, Ford L (2024) N-desethyl isotonitazene detected in polydrug users admitted to hospital in Birmingham, United Kingdom. Clin Toxicol 62:19\u201325. https:\/\/doi.org\/10.1080\/15563650.2024.2309321","journal-title":"Clin Toxicol"},{"key":"3774_CR52","unstructured":"Reavy P (2003) Utah case of potent drug is US first. In: Deseret news. https:\/\/www.deseret.com\/2003\/6\/3\/19726293\/utah-case-of-potent-drug-is-u-s-first. Accessed 27 July 2023"},{"key":"3774_CR53","doi-asserted-by":"publisher","first-page":"5530","DOI":"10.2174\/1381612823666170622111739","volume":"23","author":"C Sastre","year":"2017","unstructured":"Sastre C, Bartoli C, Baillif-Couniou V et al (2017) Post mortem redistribution of drugs: current state of knowledge. Curr Pharm Des 23:5530\u20135541. https:\/\/doi.org\/10.2174\/1381612823666170622111739","journal-title":"Curr Pharm Des"},{"key":"3774_CR54","first-page":"20","volume":"9","author":"VI Sorokin","year":"1999","unstructured":"Sorokin VI (1999) Illegal synthesis of etonitazene. J Clan Lab Invest Chem Assoc 9:20","journal-title":"J Clan Lab Invest Chem Assoc"},{"key":"3774_CR55","first-page":"239","volume":"32","author":"VI Sorokin","year":"1999","unstructured":"Sorokin VI, Ponkratov KV, Drozdov MA (1999) Etonitazene encountered in Moscow. Microgram 32:239","journal-title":"Microgram"},{"key":"3774_CR77","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-024-03735-0","author":"O Taoussi","year":"2024","unstructured":"Taoussi O, Berardinelli D, Zaami S et al (2024) Human metabolism of four synthetic benzimidazole opioids: isotonitazene, metonitazene, etodesnitazene, and metodesnitazene. Arch Toxicol. https:\/\/doi.org\/10.1007\/s00204-024-03735-0","journal-title":"Arch Toxicol"},{"key":"3774_CR56","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1021\/acschemneuro.3c00750","volume":"15","author":"M-HM Tsai","year":"2024","unstructured":"Tsai M-HM, Chen L, Baumann MH et al (2024) In vitro functional profiling of fentanyl and nitazene analogs at the \u03bc-opioid receptor reveals high efficacy for Gi protein signaling. ACS Chem Neurosci 15:854\u2013867. https:\/\/doi.org\/10.1021\/acschemneuro.3c00750","journal-title":"ACS Chem Neurosci"},{"key":"3774_CR57","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1021\/acschemneuro.1c00037","volume":"12","author":"I Ujv\u00e1ry","year":"2021","unstructured":"Ujv\u00e1ry I, Christie R, Evans-Brown M et al (2021) DARK classics in chemical neuroscience: etonitazene and related benzimidazoles. ACS Chem Neurosci 12:1072\u20131092. https:\/\/doi.org\/10.1021\/acschemneuro.1c00037","journal-title":"ACS Chem Neurosci"},{"key":"3774_CR58","unstructured":"UNODC (1975) The international drug control conventions: schedules of the single convention on narcotic drugs of 1961, as amended by the 1972 protocol"},{"key":"3774_CR59","volume-title":"vol 24","author":"UNODC (2020) The growing complexity of the opioid crisis. Global SMART update","year":"2020","unstructured":"UNODC (2020) The growing complexity of the opioid crisis. Global SMART update (2020) vol 24. Austria, Vienna"},{"key":"3774_CR60","unstructured":"UNODC (2021) CND decision on international control of isotonitazene enters into force. https:\/\/www.unodc.org\/LSS\/announcement\/Details\/65247392-26c7-4446-a2b6-270226103036. Accessed 28 July 2023"},{"key":"3774_CR61","unstructured":"UNODC (2022a) Booklet 4\u2014drug market trends of cocaine, amphetamine-type stimulants and new psychoactive substances. In: World drug report. 2022. https:\/\/www.unodc.org\/unodc\/en\/data-and-analysis\/world-drug-report-2022.html. Accessed 26 July 2023"},{"key":"3774_CR62","unstructured":"UNODC (2022b) CND decision on international control of brorphine and metonitazene enters into force\u2014remaining decisions will enter into force in November 2022. https:\/\/www.unodc.org\/LSS\/Announcement\/Details\/a56e0bd9-0da5-4152-a34d-7cff7746bf50. Accessed 1 Aug 2023"},{"key":"3774_CR63","unstructured":"UNODC (2023) CND decision on international control of 2-methyl-AP-237, etazene, etonitazepyne, protonitazene enters into force. https:\/\/www.unodc.org\/LSS\/Announcement\/Details\/89971a21-31d2-4f8a-8f28-e06f27c712ea. Accessed 1 Aug 2023"},{"key":"3774_CR64","doi-asserted-by":"publisher","first-page":"3819","DOI":"10.1007\/s00204-020-02855-7","volume":"94","author":"MM Vandeputte","year":"2020","unstructured":"Vandeputte MM, Cannaert A, Stove CP (2020) In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances. Arch Toxicol 94:3819\u20133830. https:\/\/doi.org\/10.1007\/s00204-020-02855-7","journal-title":"Arch Toxicol"},{"key":"3774_CR65","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1021\/acschemneuro.1c00064","volume":"12","author":"MM Vandeputte","year":"2021","unstructured":"Vandeputte MM, Van Uytfanghe K, Layle NK et al (2021) Synthesis, chemical characterization, and \u03bc-opioid receptor activity assessment of the emerging group of \u201cnitazene\u201d 2-benzylbenzimidazole synthetic opioids. ACS Chem Neurosci 12:1241\u20131251. https:\/\/doi.org\/10.1021\/acschemneuro.1c00064","journal-title":"ACS Chem Neurosci"},{"key":"3774_CR66","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1093\/jat\/bkab082","volume":"46","author":"MM Vandeputte","year":"2022","unstructured":"Vandeputte MM, Krotulski AJ, Papsun DM et al (2022a) The rise and fall of isotonitazene and brorphine: two recent stars in the synthetic opioid firmament. J Anal Toxicol 46:115\u2013121. https:\/\/doi.org\/10.1093\/jat\/bkab082","journal-title":"J Anal Toxicol"},{"key":"3774_CR67","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1007\/s00204-022-03276-4","volume":"96","author":"MM Vandeputte","year":"2022","unstructured":"Vandeputte MM, Krotulski AJ, Walther D et al (2022b) Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole \u2018nitazene\u2019 synthetic opioid. Arch Toxicol 96:1845\u20131863. https:\/\/doi.org\/10.1007\/s00204-022-03276-4","journal-title":"Arch Toxicol"},{"key":"3774_CR68","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1007\/s00204-021-03207-9","volume":"96","author":"MM Vandeputte","year":"2022","unstructured":"Vandeputte MM, Persson M, Walther D et al (2022c) Characterization of recent non-fentanyl synthetic opioids via three different in vitro \u00b5-opioid receptor activation assays. Arch Toxicol 96:877\u2013897. https:\/\/doi.org\/10.1007\/s00204-021-03207-9","journal-title":"Arch Toxicol"},{"key":"3774_CR69","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2022.108161","volume":"235","author":"MM Vandeputte","year":"2022","unstructured":"Vandeputte MM, Vasudevan L, Stove CP (2022d) In vitro functional assays as a tool to study new synthetic opioids at the \u03bc-opioid receptor: potential, pitfalls and progress. Pharmacol Ther 235:108161. https:\/\/doi.org\/10.1016\/j.pharmthera.2022.108161","journal-title":"Pharmacol Ther"},{"key":"3774_CR70","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1007\/s00204-022-03294-2","volume":"96","author":"MM Vandeputte","year":"2022","unstructured":"Vandeputte MM, Verougstraete N, Walther D et al (2022e) First identification, chemical analysis and pharmacological characterization of N-piperidinyl etonitazene (etonitazepipne), a recent addition to the 2-benzylbenzimidazole opioid subclass. Arch Toxicol 96:1865\u20131880. https:\/\/doi.org\/10.1007\/s00204-022-03294-2","journal-title":"Arch Toxicol"},{"key":"3774_CR71","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2023.109939","volume":"249","author":"MM Vandeputte","year":"2023","unstructured":"Vandeputte MM, Tsai M-HM, Chen L et al (2023) Comparative neuropharmacology of structurally distinct non-fentanyl opioids that are appearing on recreational drug markets worldwide. Drug Alcohol Depend 249:109939. https:\/\/doi.org\/10.1016\/j.drugalcdep.2023.109939","journal-title":"Drug Alcohol Depend"},{"key":"3774_CR72","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.113910","volume":"177","author":"L Vasudevan","year":"2020","unstructured":"Vasudevan L, Vandeputte M, Deventer M et al (2020) Assessment of structure-activity relationships and biased agonism at the Mu opioid receptor of novel synthetic opioids using a novel, stable bio-assay platform. Biochem Pharmacol 177:113910. https:\/\/doi.org\/10.1016\/j.bcp.2020.113910","journal-title":"Biochem Pharmacol"},{"key":"3774_CR73","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1093\/jat\/bkab117","volume":"46","author":"SE Walton","year":"2021","unstructured":"Walton SE, Krotulski AJ, Logan BK (2021) A forward-thinking approach to addressing the new synthetic opioid 2-benzylbenzimidazole nitazene analogs by liquid chromatography\u2013tandem quadrupole mass spectrometry (LC\u2013QQQ-MS). J Anal Toxicol 46:221\u2013231. https:\/\/doi.org\/10.1093\/jat\/bkab117","journal-title":"J Anal Toxicol"},{"key":"3774_CR74","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/s00213-022-06292-5","volume":"240","author":"SE Walton","year":"2023","unstructured":"Walton SE, Krotulski AJ, Glatfelter GC et al (2023) Plasma pharmacokinetics and pharmacodynamic effects of the 2-benzylbenzimidazole synthetic opioid, isotonitazene, in male rats. Psychopharmacology 240:185\u2013198. https:\/\/doi.org\/10.1007\/s00213-022-06292-5","journal-title":"Psychopharmacology"},{"key":"3774_CR75","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/aps.2011.173","volume":"33","author":"R Zhang","year":"2012","unstructured":"Zhang R, Xie X (2012) Tools for GPCR drug discovery. Acta Pharmacol Sin 33:372\u2013384. https:\/\/doi.org\/10.1038\/aps.2011.173","journal-title":"Acta Pharmacol Sin"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-024-03774-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-024-03774-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-024-03774-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T10:05:50Z","timestamp":1723629950000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-024-03774-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,14]]},"references-count":82,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,9]]}},"alternative-id":["3774"],"URL":"https:\/\/doi.org\/10.1007\/s00204-024-03774-7","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,14]]},"assertion":[{"value":"20 March 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}