Abstract
New psychoactive substances (NPS) appear on the recreational market on a monthly basis, with unclear toxicology, resulting in an increasing number of fatalities. Identification of drug targets and potencies is crucial for understanding and treating intoxications and for scheduling processes. In this study 60 NPS and metabolites belonging to opioids, cannabinoids and serotonergic hallucinogens classes were screened for in vitro activation of the μ-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 μ-opioid and 5-HT2A receptors, respectively.Most substances activated their corresponding target receptor. The most potent μ-opioid receptor agonists were 2-fluorofentanyl (EC50 = 1.0 nM), carfentanil (EC50 = 2.7 nM) and acrylfentanyl (EC50 = 2.8 nM) and in total a >1500-fold difference was seen among the tested compounds. Moreover, furanylfentanyl, 4-methoxybutyrylfentanyl and valerylfentanyl acted as partial agonists of the μ-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 μ-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.
Highlights
Every year a large number of new psychoactive substances (NPS) appear on the recreational drug market
Compounds of eight major classes of NPS, as categorized by the EMCDDA [3], were screened against the four human receptors m-opioid, CB1, 5-HT1A and 5-HT2A, the results are shown in Table 2 for the 7.5 mg/mL concentration
NPS classified as opioids, cannabinoids, cathinones, phenethylamines, piperazines, tryptamines, benzodiazepines and other substances were screened for GPCR activity on the m-opioid, CB1, 5-HT1A and 5-HT2A receptors
Summary
Every year a large number of new psychoactive substances (NPS) appear on the recreational drug market. 2-fluorofentanyl 1P-LSD 25B-NBOMe 25E-NBOMe 25I-NBOMe *25N-NBOMe 25T4-NBOMe 2C-E 2C-I *2-Me-DMT 2-fluoromethamphetamine 3-methoxyohencyclidine (3-MeO-PCP) 4-Cl-isobutyrylfentanyl *4-metoxybutyrylfentanyl 5F-ADB 5F-AKB-48 *5-IT 5-MeO-DET 5-MeO-DPT *5-MeO-NiPT AB-FUBINACA AB-PINACA Acetylfentanyl Acrylfentanyl ADB-FUBINACA Allylescaline AM-2201 Amphetamine *α-PVP BB-22 (aka QUCHIC) Benzylpiperazine (BZP) βk-2C-B Bromo-DragonFLY Buprenorphine Butyrylfentanyl *C30-NBOMe Camfetamine *Carfentanil Cathinone Cyclopentylfentanyl XLR-11 Valerylfentanyl Cyclopropylfentanyl Deschloroetizolam Diclazepam N, N-dimethyltryptamine (DMT) DOET DOM DPT *EFLEA EG-2201 FDU-NNEI Fentanyl Flephedrone (aka 4-fluoromethcathinone, 4-FMC) *Flubromazolam Furanylethylfentanyl Furanylfentanyl (Fu-F) Isobutyrylfentanyl JWH-018 LSD MDAI MDMA MDMB-CHMCZCA *MDPV Meclonazepam 4-MeOPP Mephedrone (aka 4-methylmethcathinone, 4-MMC) Methiopropamine *Methoxypiperamide MDMB-CHMICA Morphine *MT-45 Ocfentanil PB-22 3-carboxy indole PB-22 N-pentanoic acid-3-carboxy indole Vendor. Vendor name PTI-2 Pyrazolam TCB2 Tetrahydrofuran fentanyl TFMPP THC THJ-018 U47700 25I-NBOMe metabolite CHM-003 DL-2-Methylamphetamine independent of the G-protein complex in a ligand specific manner. Gprotein coupling associated signaling has been linked to analgesia and euphoria [5]
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