Identification of MDMB-FUBINACA in commercially available e-liquid formulations sold for use in electronic cigarettes

Peace, Michelle R.; Krakowiak, Ireneusz; Wolf, Carl E.; Poklis, Alphonse; Poklis, Justin L.

doi:10.1016/j.forsciint.2016.12.031

Cited by 45 publications

(27 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MMB-FUBINACA is also suspected of being involved in the deaths of 20 people in New Zealand (https://interactives.stuff.co.nz/2017/09/killer-chemicals/). MDMB-FUBINACA was recently detected in three different commercially available e-liquids acquired online (Peace et al, 2017). NNEI is as a novel synthetic cannabinoid originally with the aminoalkylindole class as a basis, but it contains a carboxamide linker (Blaazer et al, 2011).…”

Section: Downloaded Frommentioning

confidence: 99%

Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA

Gamage

Farquhar

Lefever

et al. 2018

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Synthetic cannabinoids are a class of novel psychoactive substances that exhibit high affinity at the cannabinoid type-1 (CB) receptor and produce effects similar to those of Δ-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. Illicit drug manufacturers are continually circumventing laws banning the sale of synthetic cannabinoids by synthesizing novel structures and doing so with little regard for the potential impact on pharmacological and toxicological effects. Synthetic cannabinoids produce a wide range of effects that include cardiotoxicity, seizure activity, and kidney damage, and they can cause death. Six synthetic cannabinoids, recently detected in illicit preparations, MMB-FUBINACA, MDMB-FUBINACA, CUMYL-PICA, 5F-CUMYL-PICA, NNEI, and MN-18 were assessed for: 1) receptor binding affinity at the human CB and human CB receptors, 2) function in [S]GTPS and cAMP signaling, and 3) THC-like effects in a mouse drug discrimination assay. All six synthetic cannabinoids exhibited high affinity for human cannabinoid receptors type-1 and type-2 and produced greater maximal effects than THC in [S]GTPS and cAMP signaling. Additionally, all six synthetic cannabinoids substituted for THC in drug discrimination, suggesting they probably possess subjective effects similar to those of cannabis. Notably, MDMB-FUBINACA, a methylated analog of MMB-FUBINACA, had higher affinity for CB than the parent, showing that minor structural modifications being introduced can have a large impact on the pharmacological properties of these drugs. This study demonstrates that novel structures being sold and used illicitly as substitutes for cannabis are retaining high affinity at the CB receptor, exhibiting greater efficacy than THC, and producing THC-like effects in models relevant to subjective effects in humans.

show abstract

Section: Downloaded Frommentioning

confidence: 99%

Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA

Gamage

Farquhar

Lefever

et al. 2018

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…In GTPgS binding assay FUB was found to be 20-fold more potent compared to D 9 -THC (Gamage et al, 2018). Although toxicity of FUB consumption has not been determined directly, Fubinacas have been linked to thousands of hospitalizations and numerous fatalities (Adams et al, 2017;Peace et al, 2017). While synthetic cannabinoids have been shown to have multiple targets, they predominantly signal through CB1.…”

Section: Introductionmentioning

confidence: 99%

Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex

Kumar

Shalev-Benami

Robertson

et al. 2019

Cell

347

322

View full text Add to dashboard Cite

Graphical AbstractHighlights d 3 Å cryo-EM structure of the CB1-G i complex bound to potent agonist MDMB-Fubinaca d MDMB-Fubinaca locks ''toggle switch'' residues F200 3.36 / W356 6.48 in active conformation d Quantum mechanics calculations reveal the mechanism for the high affinity of Fubinaca d Molecular dynamic simulations reveal a path for ligand entry between TM1 and TM7 In BriefLooking at how a toxic, synthetic ligand locks cannabinoid receptor 1 into a signaling conformation points to ways to understand and modulate receptor activity. SUMMARYCannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein G i . Activation of CB1-G i signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of G i activation by CB1. Here, we present the structure of the CB1-G i signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities. The structure illustrates how FUB stabilizes the receptor in an active state to facilitate nucleotide exchange in G i . The results compose the structural framework to explain CB1 activation by different classes of ligands and provide insights into the G protein coupling and selectivity mechanisms adopted by the receptor.

show abstract

“…This paper reports on a new phenomenon first observed in 2015—e-liquids laced with synthetic cannabinoids. In 2016 e-liquids containing MDMB-FUBINACA were identified in the USA [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

5F-Cumyl-PINACA in ‘e-liquids’ for electronic cigarettes: comprehensive characterization of a new type of synthetic cannabinoid in a trendy product including investigations on the in vitro and in vivo phase I metabolism of 5F-Cumyl-PINACA and its non-fluorinated analog Cumyl-PINACA

et al. 2018

View full text Add to dashboard Cite

PurposeIn recent years e-liquids used in electronic cigarettes have become an attractive alternative to smoking tobacco. A new trend is the use of e-liquids containing synthetic cannabinoids (SCs) instead of smoking cannabis or herbal mixtures laced with SCs. In the frame of a systematic monitoring of the online market of ‘legal high’ products, e-liquids from online retailers who also sell herbal blends were bought.MethodsThe products were analyzed by gas chromatography-mass spectrometry. In some of the e-liquids an unknown compound was detected which was identified as the SC 5F-Cumyl-PINACA (1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide) by nuclear magnetic resonance analysis. To investigate the phase I metabolism of this new class of compounds, 5F-Cumyl-PINACA and its non-fluorinated analog Cumyl-PINACA were incubated with pooled human liver microsomes (pHLM). Cumyl-PINACA was additionally ingested orally (0.6 mg) by a volunteer in a controlled self-experiment. To assess the relative potency of Cumyl-PINACA a set of SCs were characterized using a cAMP assay.ResultsMetabolism of 5F-Cumyl-PINACA and Cumyl-PINACA showed similarities with AM-2201 and JWH-018. The main metabolites were formed by hydroxylation at the N-pentyl side chain. The main metabolites detected in the volunteer’s urine sample were the same as in the pHLM assay. All SCs tested with the cAMP assay were full agonists at the CB1 receptor. Cumyl-PINACA was the most potent SC among the tested compounds and showed an EC50 value of 0.06 nM.ConclusionsThe increasing popularity of e-liquids particularly among young people, and the extreme potency of the added SCs, pose a serious threat to public health. To our knowledge, this is the first report describing the tentative identification of human in vivo metabolites of Cumyl-PINACA and 5F-Cumyl-PINACA.Electronic supplementary materialThe online version of this article (10.1007/s11419-018-0451-8) contains supplementary material, which is available to authorized users.

show abstract

Identification of MDMB-FUBINACA in commercially available e-liquid formulations sold for use in electronic cigarettes

Cited by 45 publications

References 16 publications

Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA

Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA

Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex

5F-Cumyl-PINACA in ‘e-liquids’ for electronic cigarettes: comprehensive characterization of a new type of synthetic cannabinoid in a trendy product including investigations on the in vitro and in vivo phase I metabolism of 5F-Cumyl-PINACA and its non-fluorinated analog Cumyl-PINACA

Contact Info

Product

Resources

About