The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F‐PY‐PICA, 5F‐PY‐PINACA, and their analogs

Banister, Samuel D.; Kevin, Richard C.; Martin, L.; Adams, Axel; Macdonald, Courtney; Manning, Jamie J.; Boyd, Rochelle; Cunningham, Michael E.; Stevens, Marc Y.; McGregor, Iain S.; Glass, Michelle; Connor, Mark; Gerona, Roy

doi:10.1002/dta.2583

Cited by 16 publications

(35 citation statements)

References 49 publications

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“…( R )-AMB-FUBINACA tested in this study was more potent than any other ( R )-enantiomer in this study and was more potent than both the indazole-3-carboxamides, ( S )-JWH-018 (control, this study) and ( S )-AB-PINACA (6) and the indole-3-carboxamides 5F-AMB-PICA and 5F-PY-PICA analyzed previously using the same assay under the same conditions (Noble et al, 2019). The latter compound has been found to have little or no CB 1 activity, a finding confirmed by Banister et al (2019a).…”

Section: Resultsmentioning

confidence: 55%

“…In 2015, the production and export of 116 NPS were controlled by China including 39 SCRAs (UNODC, 2015) and soon after many of these, if not all, disappeared from the market. These compounds were rapidly replaced by new analogs, and in many but not all cases, these new substances have generally been more potent (Banister and Connor, 2018b; Banister et al, 2019a,b; Noble et al, 2019). It is therefore important to develop robust and adaptable methodologies to carry out detailed analytical and pharmacological profiling of new substances as they appear on the illicit drug market and to determine the relative theoretical potency of materials containing SCRAs at all levels of the supply chain for harm reduction purposes.…”

Section: Introductionmentioning

confidence: 99%

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Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples

et al. 2019

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Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB 1 and CB 2 receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC 50 (a measure of potency) and E max (a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB 2 receptor than at the CB 1 receptor and ( S )-enantiomers had an enhanced potency to both receptors over the ( R )-enantiomers. The relative potency of the enantiomers to the CB 2 receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of ( R )-enantiomers in seized samples. Lux® Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux® i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) ≥ 1.99. Achiral GC-MS analysis of seized herbal materials ( n = 16), found 5F-MDMB-PINACA (<1.0–91.5 mg/g herbal material) and AMB-FUBINACA (15.5–58.5 mg/g herbal material), respectively. EMB-FUBINACA, AMB-CHMICA, 5F-ADB-PINACA isomer 2, and ADB-CHMINACA were also tentatively identified. Analysis using chiral chromatography coupled to photodiode array and quadrupole time of flight mass spectrometry (chiral HPLC-PDA-QToF-MS/MS) confirmed that the ( S )-enantiomer predominated in all samples (93.6–99.3% (S)-enantiomer). Small but significant differences in synthesis precursor enantiopurity may provide significant differences between synthesis batches or suppliers and warrants further study. A method to compare potency between samples containing different SCRAs at varying concentrations was developed and applied in this small preliminary study. A 10-fold difference in the “intrinsic” potency of samples in the study was noted. With the known heterogeneity of SCRA infused materials, the approach provides a simplified method for assessing and communicating the risk of their use.

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Section: Resultsmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples

et al. 2019

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“…In vitro studies showed that various metabolites of synthetic cannabinoids retain some cannabimimetic activity, indicating that they could contribute to the pharmacological effects of the drugs (Longworth et al 2017). In contrast, some substances that are promoted as cannabinoid designer drugs have only low in vitro affinity for cannabinoid receptors and fail to exert significant cannabinoid activity in vivo, thus calling into question their classification as synthetic cannabinoids (Banister et al 2019b). Only a few synthetic cannabinoids have been studied to date with regard to their interactions with noncannabinoid targets, with low or no affinity for most major neurotransmitter receptors (Wiley et al 2016).…”

Section: Mechanism Of Action Of Synthetic Cannabinoidsmentioning

confidence: 99%

Designer drugs: mechanism of action and adverse effects

2020

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Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at l-opioid receptors and c-aminobutyric acid-A (GABA A) or GABA B receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-D-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB 1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT 2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.

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“…Two related compounds, MDMB-FUBINACA and 5-fluoro AMB, have similarly been shown to produce profound hypothermic responses in Long-Evans rats at these doses 15 . Structural analogues of these ligands, such as XLR-11 39 , 5-fluoro CUMYL-P7AICA 16 , CUMYL-4CN-BINACA 40 , and AB-CHMINACA, and AB-PINACA 41 have shown similar cannabimimetic effects in rodent models—including profound hypothermia and pro-convulsant effects. Here, in vitro and in silico experiments utilized human CB1R and CB2R, whereas in vivo experiments were conducted in mice, which represents a limitation of our study.…”

Section: Discussionmentioning

confidence: 99%

Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

Zagzoog

Brandt

Black

et al. 2021

Sci Rep

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The first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs—JWH-018 2′-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.

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The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F‐PY‐PICA, 5F‐PY‐PINACA, and their analogs

Cited by 16 publications

References 49 publications

Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples

Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples

Designer drugs: mechanism of action and adverse effects

Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

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