Identification of (1-pentylindol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone and its 5-pentyl fluorinated analog in herbal incense seized for drug trafficking

Four herbal incense products were seized from suspected drug abusers in Korea. The major ingredients in the herbal incense samples were purified, and their structures were elucidated using gas chromatography–electron ionization–mass spectrometry (GC–EI–MS), liquid chromatography–time-of-flight–mass spectrometry (LC–TOF–MS), and 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. As a result, ingredients in the herbal incense were identified as (1-pentylindol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone and its 5-pentyl fluorinated analog [1-(5-fluoropentyl)indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl)methanone. The former is being sold via the Internet as a "research chemical" named UR-144, and the latter is sold as 5F-UR-144. UR-144 is a selective full agonist of CB₂ cannabinoid receptor, and was first developed by Abbott Laboratories as an analgesic. It exhibits analgesic activity against both neuropathic and inflammatory pain associated mainly with the CB₂ receptor, but shows less psychotropic effects associated with the CB₁ receptor. Fluorination of the N-pentyl side chain of cannabimimetic compounds increases their cannabinoid receptor affinity such as with AM-2201, which shows both increased analgesic and psychotropic effects simultaneously. UR-144 and 5F-UR-144 can be classified as research chemicals based on their analgesic effects, but in practice are abused as psychotropic agents and can cause unexpected toxic effects. Thus, the trade and diversion of these chemicals should be monitored carefully for possible abuse. To our knowledge, this is the first report disclosing cyclopropylcarbonylindoles in herbal products.     

New cannabimimetic indazole derivatives, N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA) and N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA) identified as designer drugs in illegal products

Two new cannabimimetic indazole derivatives, N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA, 1) and N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA, 2), have been identified as designer drugs in illegal products. These identifications were based on liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy. Because there have been neither chemical nor pharmacological data about compound 1 until now, this is the first report of this compound. Compound 2 was reported as a potent cannabinoid CB₁ receptor modulator when synthesized by Pfizer in 2009; but this is the first report of its detection in illegal products.     

Identification of (1<Emphasis Type="Italic">H</Emphasis>-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (DP-UR-144) in a herbal drug product that was commercially available in the Tokyo metropolitan area

We encountered during our investigation a case of herbal drug products commercially available in the Tokyo metropolitan area in 2014, in which a small unknown peak was detected, along with the intense peak of FUB-144, by liquid chromatography–ultraviolet detection. The present study was conducted to identify and clarify the pharmacological characteristics of the compound present in this small peak. We isolated a compound using a silica gel column from the peak, which was then identified to have a molecular weight of 241 Da by liquid chromatography–mass spectrometry and gas chromatography–mass spectrometry. The accurate mass measurement suggested an elementary composition of C₁₆H₁₉NO. Using these mass data together with those obtained by the nuclear magnetic resonance analysis, the compound was finally identified as (1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (despentyl-UR-144; DP-UR-144). In addition, this compound was revealed to have affinities for cannabinoid receptors CB₁ and CB₂ with EC₅₀s of 2.36 × 10^?6 and 2.79 × 10^?8 M, respectively. To our knowledge, there is no information in the scientific literature on structural or pharmacological properties of this chemical. These results suggest that the components present in small amounts can contribute to the effects of a major component in their mother product, if they have sufficient pharmacological activities, and, therefore, even such small amounts of components should be precisely characterized and well evaluated to control illegal and potentially illegal drug products.     

Identification of the synthetic cannabinoid <Emphasis Type="Italic">N</Emphasis>-(2-phenyl-propan-2-yl)-1-(4-cyanobutyl)-1<Emphasis Type="Italic">H</Emphasis>-indazole-3-carboxamide (CUMYL-4CN-BINACA) in a herbal mixture product

We were the first to detect N-(2-phenylpropan-2-yl)-1-(4-cyanobutyl)-1H-indazole-3-carboxamide (common name CUMYL-4CN-BINACA) as a new synthetic cannabinoid, on the illegal market in Bursa, Turkey. To elucidate the chemical structure, the dried herbal mixture was extracted with methanol. The extract was purified by column chromatography. Pure compound was analyzed by gas chromatography–mass spectrometry (GC–MS), attenuated total reflection Fourier-transform infrared spectroscopy (FT-IR), and one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. The GC–MS, FT-IR and ¹H and ¹³C NMR spectra of the compound coincided well with the reference data. All protons and carbons were assigned by their couplings and correlations observed in ¹H-¹H correlation spectroscopy, ¹H-¹³C heteronuclear multiple bond correlation, and ¹H-¹³C heteronuclear single quantum coherence spectra. On the basis of the spectral data, the compound was identified as CUMYL-4CN-BINACA. Herewith, we report analytical characteristics of CUMYL-4CN-BINACA enabling its (and possible analogues thereof) determination in criminal seizures.     

In vitro and in vivo metabolisms of 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122)

1-Pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122) is an agonist of the cannabinoid receptors CB₁ and CB₂. In this study, the phase I and phase II metabolisms of JWH-122 were investigated using two models. In vitro studies using incubations of JWH-122 with human liver microsomes were performed to obtain metabolites of the drug at the initial step; 11 classes of metabolites were found and analyzed by liquid chromatography–mass spectrometry (LC–MS) and liquid chromatography–tandem mass spectrometry (LC–MS–MS). Hydroxylation(s) on the naphthalene moiety and/or the indole moiety of the molecule took place as such or in combination with dehydrogenation or cleavage of the N-pentyl side chain. Furthermore, dihydrodiol metabolites were formed probably via epoxide formation on the naphthalene moiety, irrespective of the combination with hydroxylation(s). A metabolite carrying a carboxyl group on the N-pentyl side chain was also detected. As the second step of the study, in vivo experiments using chimeric mice were performed; the mice were orally administered JWH-122, and their urine samples were collected, subjected to enzymatic hydrolysis, and analyzed by LC–MS and LC–MS–MS. The urine samples without hydrolysis were also analyzed for their molecular formulae in the conjugated forms by LC–high resolution MS. The in vivo model using chimeric mice confirmed most metabolite classes and clarified the phase II metabolism of JWH-122. It was concluded that all metabolites formed in vivo were excreted conjugated as glucuronide or sulfate, with conjugation rates above 50 %.     

Cannabimimetic activities of cumyl carboxamide-type synthetic cannabinoids

1-Pentyl-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide (CUMYL-PINACA) is a carboxamide-type synthetic cannabinoid comprising a cumylamine moiety. Recently, the detection of CUMYL-PINACA and some analogs in illicit drug products has been reported by the European Monitoring Centre for Drugs and Drug Addiction. In this study, we synthesized seven cumyl carboxamide-type synthetic cannabinoids (CUMYL-PINACA, CUMYL-5F-PINACA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-THPINACA, CUMYL-BICA, and CUMYL-5F-P7AICA) and evaluated their activities as CB₁ and CB₂ receptor agonists. We also showed the analytical characterization of these compounds using gas chromatography–electron ionization-mass spectrometry. All of the evaluated compounds exhibited moderate to strong activities as agonists acting on both CB₁ and CB₂ receptors with EC₅₀ values in the range of 8.1 × 10^?10–7.8 × 10^?7 mol/L for CB₁ and from 2.5 × 10^?10 to 9.1 × 10^?6 mol/L for CB₂. The EC₅₀ data presented will be helpful to understand the effects of these compounds in the forensic cases. Furthermore, other new cumyl carboxamide-type synthetic cannabinoids, which will be potentially distributed in the future, will probably have the activities as agonists acting on both CB₁ and CB₂ receptors.     

Comprehensive analytical and structural characteristics of methyl 3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-indazole-3-carboxamido)butanoate (MDMB-4en-PINACA)

Purpose

The purpose of the study was to evaluate a complete analytical and structural characterization of methyl 3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-indazole-3-carboxamido)butanoate (MDMB-4en-PINACA), a novel synthetic cannabinoid being the analogue of 5F-ADB.

Methods

The compound was analyzed by gas chromatography–mass spectrometry (GC–MS), high-resolution liquid chromatography–mass spectrometry (LC–MS), X-ray diffraction and spectroscopic methods, such as nuclear magnetic resonance (NMR) and Fourier-transform infrared (FTIR) spectroscopies. To derive MDMB-4en-PINACA molecular geometry and to assign infrared absorption bands, quantum calculations with the employment of density functional theory were also used.

Results

We present a wide range of chromatographic and spectroscopic data supported with theoretical calculations allowing to identify MDMB-4en-PINACA.

Conclusions

To our knowledge, this is the first report presenting a comprehensive analytical and structural characterization of MDMB-4en-PINACA obtained by 1D and 2D NMR, GC–MS, LC–MS(/MS), attenuated total reflection-FTIR spectroscopy, powder X-ray diffraction and quantum chemical calculations. The presented results not only broaden the knowledge about this psychoactive substance but also are useful for forensic and clinical purposes.

     

Identification of a synthetic cannabinoid A-836339 as a novel compound found in a product

As a part of the work conducted in our laboratory, we encountered a case in which new chemical compound was contained in a certain product. This compound was found to have a molecular weight of 310 Da by liquid chromatography–mass spectrometry and gas chromatography–mass spectrometry. Accurate mass spectrometry measurements showed that the compound had an elemental composition of C₁₆H₂₆N₂O₂S. Using these mass data together with those obtained by nuclear magnetic resonance analysis and X-ray crystallographic analysis, this compound was identified as N-[3-(2-methoxyethyl)-4,5-dimethyl-2(3H)-thiazolylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide, which was reported in 2009 and named A-836339. It was described as a thiazol derivative and a selective agonist of G-protein-coupled cannabinoid receptor CB₂. This is the first report to identify this compound in a dubious product.     

Identification of new synthetic cannabinoid analogue APINAC (adamantan-1-yl 1-pentyl-1H-indazole-3-carboxylate) with other synthetic cannabinoid MDMB(N)-Bz-F in illegal products

Two synthetic cannabinoid analogues were detected using high-performance liquid chromatography (HPLC)–diode array detector, and gas chromatography–time-of-flight-mass spectrometry during the inspection of illegal products in an airmail package. The analogues were separated by semi-preparative HPLC, and their structures were determined by performing liquid chromatography–high-resolution-mass spectrometry, infrared analysis, and nuclear magnetic resonance spectroscopy. Compound 1 was MDMB(N)-Bz-F, which has been reported previously. Compound 2 was elucidated as adamantan-1-yl 1-pentyl-1H-indazole-3-carboxylate (APINAC), in which the amide group of APINACA was replaced with an ester group. Because there has been no chemical or pharmacological data about this compound until now, this is the first report of its detection in illegal products.     

Identification of a new synthetic cannabinoid in a herbal mixture: 1-butyl-3-(2-methoxybenzoyl)indole

Two unknown cannabimimetic compounds were detected in a seized herbal mixture after gas chromatography–mass spectrometry (GC–MS) screening. To elucidate the chemical structures, 0.3 g of the dried plant material was extracted with methanol and concentrated under reduced pressure. The extract was purified by silica gel column chromatography with methylene chloride and methanol. Pure compounds were isolated by preparative high-performance liquid chromatography (HPLC) and then analyzed by electrospray ionization (ESI) mass spectrometry (MS) with direct flow injection, high-resolution ESI-time-of-flight (TOF)–MS and one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. GC–MS spectra showed that the base ion at m/z 321 for compound 1 was the same as that of 1-pentyl-3-(4-methoxybenzoyl)indole (RCS-4), and the fragment ions were almost the same as those of RCS-4. The GC–MS spectrum of compound 2 was very similar to that of compound 1 except that the mass numbers of the fragment ions at m/z 290, 200, 186, and 173 of compound 2 were equally smaller than those of compound 1 by 14 amu. From these GC–MS results, compound 1 was assumed to be the 2- or 3-methoxy isomer of RCS-4, and compound 2 was assumed to be a 1-butylindole homologue of compound 1. The ESI mass spectra showed a single peak at m/z 322.33 for compound 1 and a single peak at m/z 308.25 for compound 2, which showed the masses of the protonated ions. High-resolution TOF–MS spectra showed the accurate mass numbers of protonated molecular ions at m/z 322.180512 for compound 1 and at m/z 308.164895 for compound 2, suggesting the molecular formulas of C₂₁H₂₃NO₂ and C₂₀H₂₁NO₂, respectively. The ¹H NMR spectra showed signals that suggested 23 and 21 protons for compounds 1 and 2, respectively, while the respective ¹³C NMR spectra showed 21 and 20 carbon signals. All protons and carbons were assigned by their couplings and correlations observed in ¹H–¹H correlation spectroscopy (COSY), ¹H–¹³C heteronuclear multiple bond correlation (HMBC), and ¹H–¹³C heteronuclear single quantum coherence (HSQC) spectra. On the basis of the spectral data, compound 1 was identified as the 2-methoxy isomer of RCS-4; compound 2 was identified for the first time as 1-butyl-3-(2-methoxybenzoyl)indole. Phenazepam and 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) were also identified as coexisting drugs in the herbal mixture. The contents of compounds 1 and 2 in the mixture were calculated to be 22.4 and 3.45 mg/g, respectively.     

Identification and quantitation of two cannabimimetic phenylacetylindoles JWH-251 and JWH-250, and four cannabimimetic naphthoylindoles JWH-081, JWH-015, JWH-200, and JWH-073 as designer drugs in illegal products

Six cannabimimetic indoles have been identified as adulterants in herbal or chemical products being sold illegally in Japan, with four of the compounds being new as adulterants to our knowledge. The identifications were based on analyses using gas chromatography–mass spectrometry, liquid chromatography–mass spectrometry, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy. The first two compounds were identified as phenylacetyl indoles JWH-251 (2-(2-methylphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone; 1) and its demethyl-methoxylated analog JWH-250 (2-(2-methoxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone; 2). Compound 2 was identical to that found as an adulterant in the UK and in Germany in 2009. The third compound was naphthoylindole JWH-081 (1-(4-methoxynaphthalenyl)-(1-pentyl-1H-indol-3-yl)methanone; 3), and the fourth was JWH-073 (1-naphthalenyl(1-butyl-1H-indol-3-yl)methanone; 4), which had been identified as an adulterant in our previous study. Two additional compounds were JWH-015 (1-naphthalenyl(2-methyl-1-propyl-1H-indol-3-yl)methanone; 5) and JWH-200 (1-naphthalenyl(1-(2-(4-morpholinyl)ethyl)-1H-indol-3-yl)methanone; 6). Compounds 1–4 and 6 were reported to be synthetic cannabinoids with selective affinity for cannabinoid CB₁ receptors, while compound 5 was reported to be a selective CB₂ receptor agonist causing immunosuppressive effects without psychotropic affects. One product contained both CB₁ and CB₂ receptor agonists in our collection. Quantitative analyses of the six cannabimimetic compounds in 20 products revealed that there was large variation in concentrations of the detected compounds among products; for herbal cutting products, the total amounts of these cannabinoids ranged from 26 to 100 mg.     

The 2-alkyl-2<Emphasis Type="Italic">H</Emphasis>-indazole regioisomers of synthetic cannabinoids AB-CHMINACA,AB-FUBINACA,AB-PINACA,and 5F-AB-PINACA are possible manufacturing impurities with cannabimimetic activities

Indazole-derived synthetic cannabinoids (SCs) featuring an alkyl substituent at the 1-position and l-valinamide at the 3-carboxamide position (e.g., AB-CHMINACA) have been identified by forensic chemists around the world, and are associated with serious adverse health effects. Regioisomerism is possible for indazole SCs, with the 2-alkyl-2H-indazole regioisomer of AB-CHMINACA recently identified in SC products in Japan. It is unknown whether this regiosiomer represents a manufacturing impurity arising as a synthetic byproduct, or was intentionally synthesized as a cannabimimetic agent. This study reports the synthesis, analytical characterization, and pharmacological evaluation of commonly encountered indazole SCs AB-CHMINACA, AB-FUBINACA, AB-PINACA, 5F-AB-PINACA and their corresponding 2-alkyl-2H-indazole regioisomers. Both regioisomers of each SC were prepared from a common precursor, and the physical properties, ¹H and ¹³C nuclear magnetic resonance spectroscopy, gas chromatography–mass spectrometry, and ultraviolet–visible spectroscopy of all SC compounds are described. Additionally, AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA were found to act as high potency agonists at CB₁ (EC₅₀ = 2.1–11.6 nM) and CB₂ (EC₅₀ = 5.6–21.1 nM) receptors in fluorometric assays, while the corresponding 2-alkyl-2H-indazole regioisomers demonstrated low potency (micromolar) agonist activities at both receptors. Taken together, these data suggest that 2-alkyl-2H-indazole regioisomers of AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA are likely to be encountered by forensic chemists and toxicologists as the result of improper purification during the clandestine synthesis of 1-alkyl-1H-indazole regioisomers, and can be distinguished by differences in gas chromatography–mass spectrometry fragmentation pattern.     

Identification of N-ethyl-α-ethylphenethylamine in crystalline powder seized for suspected drug trafficking: a research chemical or a new designer drug?

A crystalline powder was found in an unclaimed lost article shipped from Vietnam to South Korea, and it was seized by narcotics agents as an item of suspicious trade. The chemical was suspected to be methamphetamine crystals, and was sent to the National Forensic Service for forensic identification. Elucidation of the chemical structure was carried out using gas chromatography–electron impact ionization–mass spectrometry, liquid chromatography–time-of-flight–mass spectrometry, and 1D and 2D nuclear magnetic resonance spectroscopy. The compound was identified as N-ethyl-α-ethylphenethylamine. Although the narcotic effect of this compound remains unverified, it may be classified as a phenethylamine-based designer drug on the basis of its structure. It appeared that the recipient of this article sought to abuse this chemical in the same way as amphetamines. There is a possibility that this chemical will be widely abused for recreational use in the near future.     

Spectroscopic and crystallographic characterization of two cathinone derivatives: 1-(4-fluorophenyl)-2-(methylamino)pentan-1-one (4-FPD) hydrochloride and 1-(4-methylphenyl)-2-(ethylamino)pentan-1-one (4-MEAP) hydrochloride

Purpose

In this study, we performed identification and physicochemical characterization of two cathinone derivatives, 4-FPD and 4-MEAP, found in market-available materials.

Methods

The compounds were characterized by electrospray ionization ion trap mass spectrometry (MS) in MS² and MS³ modes, gas chromatography–MS, infrared, Raman and ultraviolet-visible spectroscopies, X-ray crystallography, differential scanning calorimetry and nuclear magnetic resonance spectroscopy.

Results

We could obtain detailed and comprehensive physicochemical characterization of 4-FPD and 4-MEAP—new cathinone derivatives available on the designer drugs market.

Conclusions

Dynamic growth in the number of psychoactive substances available on the designer drug markets makes it compulsory to obtain analytical data allowing unequivocal identification of these drugs in the fastest possible way. In this study we presented analytical data useful in quick identification of the investigated compounds.

     

Identification and quantitation of JWH-213, a cannabimimetic indole, as a designer drug in a herbal product

In our survey of designer drugs in the Japanese market, a cannabimimetic indole was identified as a new active compound in a herbal product. The structure of this compound was elucidated by liquid chromatography–photodiode array–mass spectrometry (LC–PDA–MS), gas chromatography–mass spectrometry (GC–MS), high-resolution MS, and nuclear magnetic resonance (NMR) analyses. The compound was finally identified as (4-ethyl-1-naphthalenyl)(2-methyl-1-pentyl-1H-indol-3-yl)methanone (JWH-213), an indole-based cannabinoid receptor ligand. To our knowledge, this is the first finding of JWH-213 as a designer drug in a herbal product. The quantitative LC–PDA analysis showed that the JWH-213 content in the product was 252 mg/pack.     

Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products

Two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA, 1) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA, 2), have been identified as designer drugs in illegal products being sold in Japan. The identification was based on liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), high-resolution MS and nuclear magnetic resonance (NMR) analyses. Both mass and NMR spectrometric data revealed that 1 was 1-pentyl-N-tricyclo[3.3.1.1^3,7]dec-1-yl-1H-indole-3-carboxamide, and 2 was 1-pentyl-N-tricyclo[3.3.3.1.^3,7]dec-1-yl)-1H-indazole-3-carboxamide. Although many of the synthetic cannabinoids detected in illegal products, such as JWH-018, have a 3-carbonyl indole moiety, compounds 1 and 2 are a new type of synthetic cannabinoid having an amide and an adamantyl group, and 2 also has an indazole group in place of an indole group. There has been no synthetic, chemical, or biological information about 1 or 2 until now, making this the first report of these cannabimimetic compounds (1 and 2) as designer drugs. In addition, five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, are also described herein as newly distributed designer drugs in Japan.     

Evaluation of carboxamide-type synthetic cannabinoids as CB<Subscript>1</Subscript>/CB<Subscript>2</Subscript> receptor agonists: difference between the enantiomers

Recently, carboxamide-type synthetic cannabinoids have been distributed globally as new psychoactive substances (NPS). Some of these compounds possess asymmetric carbon, which is derived from an amide moiety composed of amino acid derivatives (i.e., amides or esters of amino acids). In this study, we synthesized both enantiomers of synthetic cannabinoids, N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(2-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA 2-fluorobenzyl isomer), N-(1-amino-1-oxo-3-phenylpropan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide (APP-CHMINACA), ethyl [1-(5-fluoropentyl)-1H-indazole-3-carbonyl]valinate (5F-EMB-PINACA), ethyl [1-(4-fluorobenzyl)-1H-indazole-3-carbonyl]valinate (EMB-FUBINACA), and methyl 2-[1-(4-fluorobenzyl)-1H-indole-3-carboxamido]-3,3-dimethylbutanoate (MDMB-FUBICA), which were reported as NPS found in Europe from 2014 to 2015, to evaluate their activities as CB₁/CB₂ receptor agonists. With the exception of (R) MDMB-FUBICA, all of the tested enantiomers were assumed to be agonists of both CB₁ and CB₂ receptors, and the EC₅₀ values of the (S)-enantiomers for the CB₁ receptors were about five times lower than those of (R)-enantiomers. (R) MDMB-FUBICA was shown to function as an agonist of the CB₂ receptor, but lacks CB₁ receptor activity. To the best of our knowledge, this is the first report to show that the (R)-enantiomers of the carboxamide-type synthetic cannabinoids have the potency to activate CB₁ and CB₂ receptors. The findings presented here shed light on the pharmacological properties of these carboxamide-type synthetic cannabinoids in forensic cases.     

MDMB-CHMICA induces thrashing behavior,bradycardia, and slow pressor response in a CB<Subscript>1</Subscript>- and CB<Subscript>2</Subscript>-receptor-dependent manner in conscious rats

Purpose

MDMB-CHMICA, a new synthetic cannabinoid (SC), has become prevalent since 2014 as an ingredient of recreational drugs. Reports on intoxication due to the drug have been increasing, which show diverse cardiovascular, psychiatric, and neuronal symptoms. Reports on sudden death and accidental death related to psychiatric disorders in MDMB-CHMICA intoxication have also increased, but the underlying mechanisms are largely unknown.

Methods

As there has been no experimental study on the drug, we investigated the effects of peripheral injection of MDMB-CHMICA in conscious rats.

Results

MDMB-CHMICA induced rapid bradycardia and a slow pressor response. Cardiovascular responses to other SCs have been shown to be inhibited only by cannabinoid receptor-1 (CB₁)-antagonists. However, the MDMB-CHMICA-induced bradycardia was inhibited not only by a CB₁-antagonist, AM281, but also by a CB₂-antagonist, AM630. Unlike other SCs, MDMB-CHMICA induced a gradual increase in mean blood pressure, which was marginally enhanced by the CB₁- and CB₂- antagonists. For the first time, we demonstrated that MDMB-CHMICA induces a thrashing hypermobile behavior in a CB₁- and CB₂-receptor-dependent manner, following catalepsy-like hypomobile behavior.

Conclusions

This unexpected response to MDMB-CHMICA may help explain the mechanisms underlying the sudden deaths and accidents associated with its use.