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In Vitro Characterization of New Psychoactive Substances at The Forensic Science International 317 (2020) 110553 Contents lists available at ScienceDirect Forensic Science International journal homepage: www.elsevier.com/locate/forsciint In vitro characterization of new psychoactive substances at the m-opioid, CB1, 5HT1A, and 5-HT2A receptors—On-target receptor potency and efficacy, and off-target effects a,1 a,b,1 a,b a,b,2 Anna Åstrand , Davide Guerrieri , Svante Vikingsson , Robert Kronstrand , a,b, ,2 Henrik Green * a Division of Drug Research, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, SE 581 85, Linköping, Sweden b Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, SE, 587 58 Linköping, Sweden A R T I C L E I N F O A B S T R A C T Article history: New psychoactive substances (NPS) appear on the recreational market on a monthly basis, with unclear Received 23 March 2020 toxicology, resulting in an increasing number of fatalities. Identification of drug targets and potencies is Received in revised form 15 October 2020 crucial for understanding and treating intoxications and for scheduling processes. In this study 60 NPS Accepted 17 October 2020 and metabolites belonging to opioids, cannabinoids and serotonergic hallucinogens classes were Available online 23 October 2020 screened for in vitro activation of the m-opioid, CB1, 5-HT1A and 5-HT2A receptors using the AequoZen cell system. Fentanyl and NBOMe analogues were chosen for full dose-response characterization of the Keywords: m-opioid and 5-HT2A receptors, respectively. m-Opioid receptor agonists Most substances activated their corresponding target receptor. The most potent m-opioid receptor 5-HT2A serotonin receptor agonists agonists were 2-fluorofentanyl (EC50 = 1.0 nM), carfentanil (EC50 = 2.7 nM) and acrylfentanyl Fentanyl analogues > Designer drugs (EC50 = 2.8 nM) and in total a 1500-fold difference was seen among the tested compounds. Moreover, New psychoactive substances (NPS) furanylfentanyl, 4-methoxybutyrylfentanyl and valerylfentanyl acted as partial agonists of the Potency m-receptor. On the 5-HT2A receptor, bromo-dragonfly showed the highest potency (EC50 = 0.05 nM, 400 times more potent than LSD), followed by most NBOMe compounds with EC50 values ranging from 0.11 nM (for 25N-NBOMe) to 1.3 nM (for 25T4-NBOMe)). Off-target activation of the m-opioid receptor was identified for piperazines, phenethylamines (in particular NBOMe and 2C compounds) and tryptamines. Moreover, the synthetic cannabinoid metabolite 3-carboxy indole PB-22 activated the 5- HT2A receptor. Bromo-dragonfly was the only compound that activated all four receptors. These results highlight the possible interplay of known and unknown NPS targets and unveil its complexity. Moreover, the detailed, quantitative information presented facilitates our further understanding of NPS toxicology. © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction monitored by the end of 2018 and 55 of these were detected for the first time during 2018 [2]. Every year a large number of new psychoactive substances The quick pace at which new substances are introduced creates (NPS) appear on the recreational drug market. United Nations a challenge for the legal authorities to keep up with the Office on Drugs and Crime (UNODC) states that between 2009 and identification and scheduling of substances as narcotics, when 2019, a total of 950 compounds were reported to the UNODC early appropriate. Moreover, novel NPS rarely undergo any biochemical warning advisory on NPS [1]. Only in Europe, 720 NPS were characterization before they are introduced on the illicit drug market and even less is known regarding their effect in vivo. The broad NPS term includes a plethora of different classes of substances and effects such as opioids, cannabinoids, cathinones, * Corresponding author at: Division of Drug Research, Department of Biomedical phenethylamines, piperazines, arylamines, tryptamines, and other and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping substances [3]. Several of these drugs target the G protein coupled University, SE 581 85, Linköping, Sweden. receptors (GPCRs), which consist of heterotrimeric seven- E-mail address: [email protected] (H. Green). 1 transmembrane proteins. Upon activation these receptors initiate These authors contributed equally to this study. 2 These authors share last authorship of this article. several intracellular signaling cascades both dependent and http://dx.doi.org/10.1016/j.forsciint.2020.110553 0379-0738/© 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). A. Åstrand, D. Guerrieri, S. Vikingsson et al. Forensic Science International 317 (2020) 110553 Table 1 A complete list of reference compounds used within the study including vendors. Compound Vendor Vendor name 2-fluorofentanyl Cayman Chemicals Ortho-Fluorofentanyl 1P-LSD Chiron 1p-LSD-tartrate 25B-NBOMe THC Pharm 25B-NBOMe 25E-NBOMe Cayman Chemicals 25E-NBOMe 25I-NBOMe Cayman Chemicals 25I-NBOMe *25N-NBOMe NFC 25N-NBOMe 25T4-NBOMe Cayman Chemicals 25T4-NBOMe 2C-E Cayman Chemicals 2C-E 2C-I Cayman Chemicals 2C-I *2-Me-DMT NFC 2-Me-DMT 2-fluoromethamphetamine Cayman Chemicals 2-fluoromethamphetamine 3-methoxyohencyclidine (3-MeO-PCP) Cayman Chemicals 3-methoxy-PCP 4-Cl-isobutyrylfentanyl Chiron Para-Chloroisobutyrylfentanyl *4-metoxybutyrylfentanyl NFC 4-Metoxibutyrfentanyl 5F-ADB Cayman Chemicals 5-fluoro-ADB 5F-AKB-48 Cayman Chemicals AKB 48 N-(5-fluoropentyl) analog *5-IT NFC 5-IT succinat 5-MeO-DET Cayman Chemicals 5-methoxy DET 5-MeO-DPT Cayman Chemicals 5-methoxy DPT *5-MeO-NiPT NFC 5-MeO-NiPT AB-FUBINACA Cayman Chemicals AB-FUBINACA AB-PINACA Cayman Chemicals AB-PINACA Acetylfentanyl Cayman Chemicals Acetyl fentanyl Acrylfentanyl Cayman Chemicals Acrylfentanyl ADB-FUBINACA Cayman Chemicals ADB-FUBINACA Allylescaline Cayman Chemicals Allylescaline AM-2201 Chiron AM-2201 Amphetamine Sigma-Aldrich Amphetamine *α-PVP NFC PVP BB-22 (aka QUCHIC) Cayman Chemicals BB-22 (aka QUCHIC) Benzylpiperazine (BZP) Sigma-Aldrich Benzylpiperazine (BZP) βk-2C-B Cayman Chemicals bk-2C-B Bromo-DragonFLY TRC Bromo Dragonfly Buprenorphine Sigma-Aldrich Buprenorphine Butyrylfentanyl Cayman Chemicals Butyryl fentanyl *C30-NBOMe NFC C30-NBOMe Camfetamine LGC Camfetamine *Carfentanil TRC Carfentanil Cathinone Sigma-Aldrich R (+)-Cathinone Cyclopentylfentanyl Chiron Cyclopentylfentanyl XLR-11 Chiron XLR11 Valerylfentanyl Cayman Chemicals Valeryl fentanyl Cyclopropylfentanyl Cayman Chemicals Cyclopropyl fentanyl Deschloroetizolam Chiron Deschloroetizolam Diclazepam LGC Diclazepam N, N-dimethyltryptamine (DMT) National Measurement Institute (NMIA) N, N-dimethyltryptamine DOET Cayman Chemicals DOET DOM Cayman Chemicals DOM DPT Cayman Chemicals DPT *EFLEA NFC EFLEA EG-2201 Cayman Chemicals EG-2201 FDU-NNEI Cayman Chemicals FDU-NNEI Fentanyl Sigma-Aldrich Fentanyl Flephedrone (aka 4-fluoromethcathinone, 4-FMC) TRC 4-Fluoroephedrone *Flubromazolam NFC Flubromazolam Furanylethylfentanyl Cayman Chemicals Furanylethylfentanyl Furanylfentanyl (Fu-F) Cayman Chemicals Furanylfentanyl Isobutyrylfentanyl Cayman Chemicals Isobutytyl fentanyl JWH-018 THC Pharm JWH-018 LSD Sigma-Aldrich LSD MDAI LGC 5,6-Methylenedioxy-2-aminoindane MDMA Cayman Chemicals MDMA MDMB-CHMCZCA Cayman Chemicals MDMB-CHMCZCA *MDPV NFC 3,4-Methylenedioxypyrovalerone Meclonazepam Chiron Meclonazepam 4-MeOPP Sigma-Aldrich 1-(4-Methoxyphenyl) piperazindihydrochloride Mephedrone (aka 4-methylmethcathinone, 4-MMC) LGC Mephedrone Methiopropamine LGC Methiopropamine *Methoxypiperamide NFC Metoxipiperamid MDMB-CHMICA Chiron MMB-CHMINACA Morphine Sigma-Aldrich Morphine *MT-45 NFC MT-45 Ocfentanil Cayman Chemicals Ocfentanil PB-22 Cayman Chemicals PB-22 3-carboxy indole 3-carboxyindole metabolite PB-22 N-pentanoic acid-3-carboxy indole Cayman Chemicals PB-22 N-pentanoic acid-3-carboxyindole 2 A. Åstrand, D. Guerrieri, S. Vikingsson et al. Forensic Science International 317 (2020) 110553 Table 1 (Continued) Compound Vendor Vendor name PTI-2 Cayman Chemicals PTI-2 Pyrazolam Cayman Chemicals Pyrazolam TCB-2 Tocris TCB2 *Tetrahydrofuranylfentanyl (THF-fentanyl) NFC Tetrahydrofuran fentanyl *TFMPP NFC TFMPP THC Sigma-Aldrich THC THJ-018 Cayman Chemicals THJ-018 *U-47,700 NFC U47700 **2-desmethoxy 25I-NBOMe Linköping University 25I-NBOMe metabolite CHM-003 2-methylamphetamine Chiron DL-2-Methylamphetamine * Seized materials characterized at National Forensic Centre (NFC), Sweden. ** synthesised material, Linköping University, PSYCHOMICS project. Purity as determined by HPLC was >92 %. independent of the G-protein complex in a ligand specific manner. analogues at the m-opioid and 5-HT2A receptors, respectively, Two examples of intracellular signaling pathways after GPCR were determined. activation is the β-arrestin recruitment and the G-protein coupled calcium release [4]. Fentanyl is thought to activate the β-arrestin 2. Materials and methods pathway of the m-opioid receptor to a greater extent than morphine [5,6] which is interesting as β-arrestin signaling of 2.1. Cell lines the m-opioid receptor is associated with respiratory depression in opioid abuse. However, biased signaling of different compounds is Irradiated, calcium sensitive AequoZen recombinant CHO-K1 not always as straight forward as initially thought. In contrast, G- cell lines expressing
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