Fourth generation of synthetic cannabinoid receptor agonists: A review on the latest insights

Background: Over the past few years, an emerging number of new psychoactive substances (NPSs) entered the illicit market. NPSs are designed to resemble the effects of classical drugs of abuse, reinforcing their effects and duration. Among the most abused NPS, synthetic cannabinoids are cannabinoid receptor agonists (SCRAs) and mimic the effect of the main psychotropic phytocannabinoid Δ9-tetrahydrocannabinol (THC). Methods: We herein reviewed the international literature to provide available information on the newest SCRAs generation. Results: Compared to the previous SCRAs generations, the structures of the last generation result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be mainly responsible for the psychoactive effects of THC and its analogues. Accordingly, these more potent cannabimimetic effects may increase the number of adverse reactions such as neurological disorders (e.g., psychosis, agitation, irritability, paranoia, confusion, and anxiety), psychiatric episodes (e.g., hallucinations, delusions, self-harm), other physical conditions (e.g., tachycardia, hypertension, arrhythmia, chest pain, nausea, vomiting, and fever) and deaths. In the last decade, more than a hundred SCRAs from different chemical classes emerged on the illicit web market. SCRAs have been thoroughly studied: they were physico-chemically characterized and pharmaco-toxicological characteristics were investigated. The last SCRAs generations include increasingly potent and toxic compounds, posing a potential health threat to consumers. Conclusion: From November 2017 to February 2021, at least 20 new “fourth-generation” SCRAs were formally reported to international drug agencies. Our understanding about the neurotoxicity of these compounds is still limited due to the lack of global data, but their potency and their toxicity are likely higher than those of the previous generations.

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Identification and Analytical Characterization of a Novel Synthetic Cannabinoid-Type Substance in Herbal Material in Europe

Molecules ◽

10.3390/molecules26040793 ◽

2021 ◽

Vol 26 (4) ◽

pp. 793

Author(s):

Emmanouil D. Tsochatzis ◽

Joao Alberto Lopes ◽

Margaret V. Holland ◽

Fabiano Reniero ◽

Giovanni Palmieri ◽

...

Keyword(s):

Mass Spectrometry ◽

Cannabinoid Receptor ◽

Analytical Data ◽

Synthetic Cannabinoids ◽

Synthetic Cannabinoid ◽

Gas Chromatography Mass Spectrometry ◽

New Psychoactive Substances ◽

Synthetic Cannabinoid Receptor Agonists ◽

Analytical Laboratories

The rapid diffusion of new psychoactive substances (NPS) presents unprecedented challenges to both customs authorities and analytical laboratories involved in their detection and characterization. In this study an analytical approach to the identification and structural elucidation of a novel synthetic cannabimimetic, quinolin-8-yl-3-[(4,4-difluoropiperidin-1-yl) sulfonyl]-4-methylbenzoate (2F-QMPSB), detected in seized herbal material, is detailed. An acid precursor 4-methyl-3-(4,4-difluoro-1-piperidinylsulfonyl) benzoic acid (2F-MPSBA), has also been identified in the same seized material. After extraction from the herbal material the synthetic cannabimimetic, also referred to as synthetic cannabinoid receptor agonists or “synthetic cannabinoids”, was characterized using gas chromatography-mass spectrometry (GC-MS), 1H, 13C, 19F and 15N nuclear magnetic resonance (NMR) and high-resolution tandem mass spectrometry (HR-MS/MS) combined with chromatographic separation. A cheminformatics platform was used to manage and interpret the analytical data from these techniques.

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An index of fatal toxicity for new psychoactive substances

Journal of Psychopharmacology ◽

10.1177/0269881118754709 ◽

2018 ◽

Vol 32 (7) ◽

pp. 793-801 ◽

Cited By ~ 7

Author(s):

Leslie A King ◽

John M Corkery

Keyword(s):

Cannabinoid Receptor ◽

Synthetic Cannabinoid ◽

New Psychoactive Substances ◽

Death Certificates ◽

Psychoactive Substances ◽

Receptor Agonists ◽

A Value ◽

Other Substances ◽

Synthetic Cannabinoid Receptor Agonists ◽

Original Reference

An index of fatal toxicity for new psychoactive substances has been developed based solely on information provided on death certificates. An updated index of fatal toxicity (Tf), as first described in 2010, was calculated based on the ratio of deaths to prevalence and seizures for the original five substances (amphetamine, cannabis, cocaine/crack, heroin and 3,4-methylenedioxymethylamphetamine)*. These correlated well with the 2010 index. Deaths were then examined for cases both where the substance was and was not found in association with other substances. This ratio (sole to all mentions; S/A) was then calculated for deaths in the period 1993 to 2016. This new measure of fatal toxicity, expressed by S/A, was well-correlated with the index Ln (Tf) of the original reference compounds. The calculation of S/A was then extended to a group of new psychoactive substances where insufficient prevalence or seizure data were available to directly determine a value of Tf by interpolation of a graph of Tf versus S/A. Benzodiazepine analogues had particularly low values of S/A and hence Tf. By contrast, γ-hydroxybutyrate/γ-butyrolactone, α-methyltryptamine, synthetic cannabinoid receptor agonists and benzofurans had a higher fatal toxicity.

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Differential activation of G-protein-mediated signalling by synthetic cannabinoid receptor agonists

10.1101/850651 ◽

2019 ◽

Author(s):

Shivani Sachdev ◽

Samuel D. Banister ◽

Marina Santiago ◽

Chris Bladen ◽

Michael Kassiou ◽

...

Keyword(s):

G Protein ◽

Molecular Mechanisms ◽

Cannabinoid Receptor ◽

Rank Order ◽

Synthetic Cannabinoid ◽

New Psychoactive Substances ◽

Differential Activation ◽

Receptor Agonists ◽

Synthetic Cannabinoid Receptor Agonists ◽

Camp Levels

AbstractSynthetic cannabinoid receptor agonists (SCRAs) are new psychoactive substances associated with acute intoxication and even death. However, the molecular mechanisms through which SCRAs may exert their toxic effects remain unclear - including the potential differential activation of G protein subtypes by CB1, a major target of SCRA. We measured CB1-mediated activation of Gαs and Gαi/o proteins by SCRAs by examining stimulation (PTX-treated) as well as inhibition (non-PTX treated) of forskolin-induced cAMP accumulation in HEK cells stably expressing CB1. Real-time measurements of stimulation and inhibition of cAMP levels were made using a BRET biosensor. We found that the maximum concentration of SCRAs tested (10 μM), increased cAMP levels 12 to 45% above that produced by forskolin alone, while the phytocannabinoid THC did not significantly alter cAMP levels in PTX-treated HEK-CB1 cells. All SCRAs had greater potency to inhibit of forskolin-induced cAMP levels than to stimulate cAMP levels. The rank order of potencies for SCRA stimulation of cAMP (Gαs) was PB-22 > 5F-MDMB-PICA > JWH-018 > AB-FUBINACA > XLR-11. By contrast, the potency of SCRAs for inhibition of cAMP (Gαi/o) was 5F-MDMB-PICA > AB-FUBINACA > PB-22 > JWH-018 > XLR-11. The different rank order of potency of the SCRAs to stimulate Gαs-like signalling compared to Gαi/o signalling suggests differences in G protein preference between SCRAs. Understanding the apparent differences among these drugs may contribute to unravelling their complex effects in humans.

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The switch from one substance-of-abuse to another: illicit drug substitution behaviors in a sample of high-risk drug users

PeerJ ◽

10.7717/peerj.9461 ◽

2020 ◽

Vol 8 ◽

pp. e9461

Author(s):

Barak Shapira ◽

Paola Rosca ◽

Ronny Berkovitz ◽

Igor Gorjaltsan ◽

Yehuda Neumark

Keyword(s):

High Risk ◽

Drug Users ◽

Drugs Of Abuse ◽

Cannabinoid Receptor ◽

Age At Onset ◽

Population Group ◽

Synthetic Cannabinoid ◽

Treatment Center ◽

Receptor Agonists ◽

Synthetic Cannabinoid Receptor Agonists

Background Substitution can be defined as the consciously motivated choice to use one drug, either licit or illicit, instead of another, due to perceptions of cost, availability, safety, legality, substance characteristics, and substance attributions. Substitution represents a potential risk to drug users, mainly when substitutes are of higher potency and toxicity. This study offers a basic conceptualization of illicit substitution behavior and describes substitution patterns among users of two highly prevalent drugs of abuse—heroin and cannabis. Methods Here, 592 high-risk drug users undergoing pharmacological and psycho-social treatment were interviewed. Patients were asked questions about current drug use, lifetime substitution, and substitution patterns. Descriptive statistics, chi-square tests of independence, and multinomial logistic regressions were used to identify and test correlates of substitution patterns for heroin and cannabis. Results Of the 592 drug users interviewed, 448 subjects (75.7%) reported having substituted their preferred drug for another illicit substance. Interviews yielded a total of 275 substitution events reported by users of cannabis, and 351 substitution events reported by users of heroin. The most frequently reported substitution substances for responders who preferred heroin were illicit non-prescribed “street” methadone (35.9%), followed by oral and transdermal prescription opioids (17.7%). For responders who preferred cannabis, substitution for synthetic cannabinoid receptor agonists (33.5%) followed by alcohol (16.0%) were the most commonly reported. Age at onset–of–use (p < 0.005), population group (p = 0.008), and attending treatment for the first time (p = 0.026) were significantly associated with reported lifetime substitution. Past-year use of stimulants, heroin, hallucinogens, methylenedioxymethamphetamine (MDMA), and novel psychoactive substances were—at the 95% confidence level—also significantly associated with reported lifetime substitution. In multivariate analysis, the odds for methadone substitution among heroin users were significantly affected by age at onset-of-use, type of treatment center, and education. Odds for substitution for synthetic cannabinoid receptor agonists among cannabis users were significantly affected by age, population group, type of treatment center, and education. Conclusion Self-substitution behavior should be considered by clinicians and policymakers as a common practice among most drugusers. Substitution for street methadone provides evidence for the ongoing diversion of this substance from Opioid Maintenance Treatment Centers, while the prominence of substitution of synthetic cannabinoids among dual-diagnosis patients should be regarded as an ongoing risk to patients that needs to be addressed by clinicians. Analysis of additional substitution patterns should provide further valuable insights into the behavior of drugusers.

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Structure-activity relationships of valine-, tert-leucine-, and phenylalanine amino acid-derived synthetic cannabinoid receptor agonists related to ADB-BUTINACA, APP-BUTINACA, and ADB-P7AICA

RSC Medicinal Chemistry ◽

10.1039/d1md00242b ◽

2021 ◽

Author(s):

Eric Sparkes ◽

Elizabeth Cairns ◽

Richard Kevin ◽

Felcia Lai ◽

Katharina Grafinger ◽

...

Keyword(s):

Amino Acid ◽

Cannabinoid Receptor ◽

Synthetic Cannabinoid ◽

New Psychoactive Substances ◽

Psychoactive Substances ◽

Structure Activity Relationships ◽

Receptor Agonists ◽

Structure Activity ◽

Synthetic Cannabinoid Receptor Agonists

Synthetic cannabinoid receptor agonists (SCRAs) remain one the most prevalent classes of new psychoactive substances (NPS) worldwide, and examples are generally poorly characterised at the time of first detection. We...

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Pharmacology and adverse effects of new psychoactive substances: synthetic cannabinoid receptor agonists

Archives of Pharmacal Research ◽

10.1007/s12272-021-01326-6 ◽

2021 ◽

Vol 44 (4) ◽

pp. 402-413

Author(s):

Eun Yong Chung ◽

Hye Jin Cha ◽

Hyun Kyu Min ◽

Jaesuk Yun

Keyword(s):

Adverse Effects ◽

Cannabinoid Receptor ◽

Synthetic Cannabinoid ◽

New Psychoactive Substances ◽

Psychoactive Substances ◽

Receptor Agonists ◽

Synthetic Cannabinoid Receptor Agonists

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Modulation of Human T-type Calcium Channels by Synthetic Cannabinoid Receptor Agonists in vitro

10.1101/2020.07.22.215434 ◽

2020 ◽

Author(s):

Chris Bladen ◽

Somayeh Mirlohi ◽

Marina Santiago ◽

Mitchell Longworth ◽

Michael Kassiou ◽

...

Keyword(s):

Calcium Channels ◽

Molecular Mechanisms ◽

Cannabinoid Receptor ◽

Synthetic Cannabinoids ◽

Synthetic Cannabinoid ◽

Hek293 Cells ◽

Channel Activity ◽

Receptor Agonists ◽

Synthetic Cannabinoid Receptor Agonists

AbstractBACKGROUND AND PURPOSEConsumption of Synthetic Cannabinoid Receptor agonists (SCRAs) is associated with severe adverse reactions including seizures, arrhythmias and death, but the molecular mechanisms surrounding SCRA toxicity are not yet established. These disease-like symptoms are also synonymous with altered T-type calcium channel activity which controls rhythmicity in the heart and brain. This study examined whether SCRAs alter T-type activity and whether this represents a possible mechanism of toxicity.EXPERIMENTAL APPROACHFluorescence-based and electrophysiology assays were used to screen 16 structurally related synthetic cannabinoids for their ability to inhibit human T-type calcium channels expressed in HEK293 cells. The most potent compounds were then further examined using patch clamp electrophysiology.KEY RESULTSMDMB-CHMICA and AMB-CHMINACA potently blocked Cav3.2 with IC50 values of 1.5 and 0.74 μM respectively. Current inhibition increased from 47 to 80% and 45 to 87% respectively when the channel was in slow-inactivated state. Both SCRAs had little effect on steady state inactivation, however MDMB-CHMICA significantly shifted the half activation potential by −7mV. Neither drug produced frequency dependent block, in contrast to the phytocannabinoid Δ9-THC.CONCLUSIONS and IMPLICATIONSSCRAs are potent agonists of CB1 receptors and can be extremely toxic, but observed toxicity also resembles symptoms associated with altered Cav3.2 activity. Many SCRAs tested were potent modulators of Cav3.2, raising the possibility that SC toxicity may be due in part to Cav3.2 modulation. This potent T-type channel modulation suggests the possibility of SCRAs as a new drug class with potential to treat diseases associated with altered T-type channel activity.

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