New synthetic cannabinoids carrying a cyclobutyl methyl side chain: Human phase‐I metabolism and data on human cannabinoid receptor 1 binding and activation of Cumyl‐CBMICA and Cumyl‐CBMINACA

In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure–activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared tetrahydrocannabinol (THC) and 14 SCs and their derivatives (naphthoylindoles, naphthoylnaphthalenes, benzoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established, and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via Y-randomization test and external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

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Synthesis and in Vitro Cannabinoid Receptor 1 Activity of Recently Detected Synthetic Cannabinoids 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.0c00644 ◽

2020 ◽

Vol 11 (24) ◽

pp. 4434-4446

Author(s):

Annelies Cannaert ◽

Eric Sparkes ◽

Edward Pike ◽

Jia Lin Luo ◽

Ada Fang ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Synthetic Cannabinoids ◽

Cannabinoid Receptor 1

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Synthetic cannabinoids induce acute lung inflammation via cannabinoid receptor 1 activation

ERJ Open Research ◽

10.1183/23120541.00121-2020 ◽

2020 ◽

Vol 6 (3) ◽

pp. 00121-2020

Author(s):

Charles N. Zawatsky ◽

Jasmina Abdalla ◽

Resat Cinar

Keyword(s):

Lung Inflammation ◽

Cannabinoid Receptor ◽

Synthetic Cannabinoids ◽

Acute Lung Inflammation ◽

Cannabinoid Receptor 1

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QSAR Model for Predicting the Cannabinoid Receptor 1 Binding Affinity and Dependence Potential of Synthetic Cannabinoids

10.20944/preprints202011.0363.v1 ◽

2020 ◽

Author(s):

Wonyoung Lee ◽

So-Jung Park ◽

Ji-Young Hwang ◽

Kwang-Hyun Hur ◽

Yong Sup Lee ◽

...

Keyword(s):

Binding Affinity ◽

Cannabinoid Receptor ◽

External Validation ◽

Synthetic Cannabinoids ◽

Qsar Model ◽

Least Squares Regression ◽

Cannabinoid Receptor 1 ◽

Qsar Modeling ◽

Activity Data

In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure-activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared 15 SCs and their derivatives (tetrahydrocannabinol [THC], naphthoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

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Chain Substituted Cannabilactones with Selectivity for the CB2 Cannabinoid Receptor

Molecules ◽

10.3390/molecules24193559 ◽

2019 ◽

Vol 24 (19) ◽

pp. 3559 ◽

Cited By ~ 1

Author(s):

Shakiru O. Alapafuja ◽

Spyros P. Nikas ◽

Thanh C. Ho ◽

Fei Tong ◽

Othman Benchama ◽

...

Keyword(s):

First Generation ◽

Cannabinoid Receptor ◽

Species Difference ◽

Synthetic Cannabinoids ◽

Side Chain ◽

Sar Studies ◽

Selective Ligands ◽

Carbon Substitution ◽

Synthetic Intermediates ◽

Cyano Groups

In earlier work, we reported a novel class of CB2 selective ligands namely cannabilactones. These compounds carry a dimethylheptyl substituent at C3, which is typical for synthetic cannabinoids. In the current study with the focus on the pharmacophoric side chain at C3 we explored the effect of replacing the C1′-gem-dimethyl group with the bulkier cyclopentyl ring, and, we also probed the chain’s length and terminal carbon substitution with bromo or cyano groups. One of the analogs synthesized namely 6-[1-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl) cyclopentyl] hexanenitrile (AM4346) has very high affinity (Ki = 4.9 nM) for the mouse CB2 receptor (mCB2) and 131-fold selectivity for that target over the rat CB1 (rCB1). The species difference in the affinities of AM4346 between the mouse (m) and the human (h) CB2 receptors is reduced when compared to our first-generation cannabilactones. In the cyclase assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC50 = 3.7 ± 1.5 nM, E(max) = 89%). We have also extended our structure-activity relationship (SAR) studies to include biphenyl synthetic intermediates that mimic the structure of the phytocannabinoid cannabinodiol.

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Phase I metabolism of the carbazole-derived synthetic cannabinoids EG-018, EG-2201, and MDMB-CHMCZCA and detection in human urine samples

Drug Testing and Analysis ◽

10.1002/dta.2398 ◽

2018 ◽

Vol 10 (9) ◽

pp. 1417-1429 ◽

Cited By ~ 10

Author(s):

Lukas Mogler ◽

Florian Franz ◽

Maurice Wilde ◽

Laura M. Huppertz ◽

Sebastian Halter ◽

...

Keyword(s):

Phase I ◽

Human Urine ◽

Synthetic Cannabinoids ◽

Urine Samples ◽

Human Urine Samples ◽

Phase I Metabolism

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The Novel Psychoactive Substance Cumyl-CH-MEGACLONE: Human Phase-I Metabolism, Basic Pharmacological Characterization and Comparison to Other Synthetic Cannabinoid Receptor Agonists with a γ-Carboline-1-One Core

Journal of Analytical Toxicology ◽

10.1093/jat/bkaa065 ◽

2020 ◽

Cited By ~ 1

Author(s):

Belal Haschimi ◽

Arianna Giorgetti ◽

Lukas Mogler ◽

Tibor Zsigmond Nagy ◽

Selina Kramer ◽

...

Keyword(s):

Mass Spectrometry ◽

Phase I ◽

Cannabinoid Receptor ◽

Receptor Activation ◽

Attenuated Total Reflection ◽

Gas Chromatography Mass Spectrometry ◽

New Psychoactive Substances ◽

Resonance Spectroscopy ◽

Phase I Metabolism ◽

Activation Assay

Abstract Synthetic cannabinoids (SC) remain one of the largest groups of new psychoactive substances on the European drug market. In December 2018, Cumyl-CH-MEGACLONE, a novel SC based on a γ-carboline-1-one core structure, was firstly identified in Hungary and later also other European countries. This work aims to reveal the pharmacological characteristics and phase-I metabolism of Cumyl-CH-MEGACLONE and compare the data to its analogs Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE. The purified substance was characterized by means of gas chromatography–mass spectrometry (GC–MS), liquid chromatography–quadrupole time-of-flight mass spectrometry (LC–QToF-MS), attenuated total reflection infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance spectroscopy. Phase-I metabolites were identified by LC–QToF-MS analysis combined with a scheduled precursor ion list of authentic urine samples and confirmed by comparison with metabolites built in vitro by pooled human liver microsome assays. Pharmacological data were obtained in a competitive ligand binding assay and a receptor activation assay at the human cannabinoid receptor 1 (hCB1). The structure of 5-cyclohexylmethyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (semisystematic name: Cumyl-CH-MEGACLONE) was identified in a herbal blend as the main active ingredient. Investigation of phase-I biotransformation of Cumyl-CH-MEGACLONE led to three monohydroxylated metabolites (M08, M10 and M13) as reliable urinary markers for proof of consumption. At the hCB1, Cumyl-CH-MEGACLONE shows high binding affinity with Ki = 1.01 nM (2.5-fold higher than JWH-018), an EC50 of 1.22 nM and high efficacy with EMAX = 143.4% above constitutive activity of the receptor (1.13-fold higher than JWH-018). Comparison to the analogs 5F-Cumyl-PEGACLONE and Cumyl-PEGACLONE (both are hCB1 full agonists carrying a 5-fluoropentyl or pentyl chain instead of the cyclohexylmethyl moiety) suggests that Cumyl-CH-MEGACLONE is more likely to resemble the pharmacologic profile of the latter one.

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