Nahoko Uchiyama

Chemical analysis of synthetic cannabinoids as designer drugs in herbal products.

Several synthetic cannabinoids were found in 44 of 46 different kinds of herbal products that are currently distributed on the illegal drug market in Japan due to their expected narcotic effects. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) analyses indicated that most of the products contained two major synthetic cannabinoids: (1RS,3SR)-3-[2-hydroxy-4-(2-methylnonan-2-yl)phenyl]cyclohexan-1-ol, renamed cannabicyclohexanol with the agreement of Pfizer Inc., and/or 1-naphthalenyl(1-pentyl-1H-indol-3-yl)methanone, named JWH-018. Oleamide (cis-9,10-octadecenoamide), which is an endogenous cannabinoid, was also detected in 7 products. Additionally, two synthetic cannabinoids were identified as minor components in some products. One was (1RS,3SR)-3-[2-hydroxy-4-(2-methyloctan-2-yl)phenyl]cyclohexan-1-ol, which is named CP-47,497 and is a homolog of cannabicyclohexanol. The other was 1-naphthalenyl(1-butyl-1H-indol-3-yl)methanone, which is named JWH-073 and is a homolog of JWH-018. These compounds were reported as synthetic cannabinoids possessing pharmacological cannabimimetic activity. The concentrations of cannabicyclohexanol, JWH-018 and oleamide in the products ranged from 1.1 to 16.9mg/g, 2.0 to 35.9mg/g and 7.6 to 210.9mg/g, respectively, and showed considerable variation. In this study, details of the analysis and identification of these synthetic cannabinoids in herbal products being sold on the Japanese drug market are described.

Identification of a cannabimimetic indole as a designer drug in a herbal product

A cannabimimetic indole has been identified as a new adulterant in a herbal product being sold illegally in Japan for its expected narcotic effect. Liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry analyses indicated that the product contained two major compounds. One was identified as a cannabinoid analog (1RS,3SR)-3-[4-(1,1-dimethyloctyl)-2-hydroxyphenyl]cyclohexan-1-ol (1) by direct comparison with the authentic compound, which we reported previously. The other compound (2) showed a molecular weight of 341 daltons, and accurate mass spectral measurements showed its elemental composition to be C24H23NO. Both mass and nuclear magnetic resonance spectrometric data revealed that 2 was 1-pentyl-3-(1-naphthoyl)indole [or naphthalen-1-yl-(1-pentylindol-3-yl)methanone] being identical to JWH-018, which was synthesized by Wiley and coworkers in 1998. This compound was reported as a potent cannabinoid receptor agonist possessing a pharmacological cannabimimetic activity.

Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products

We identified two new-type cannabimimetic quinolinyl carboxylates, quinolin-8-yl 1-pentyl-(1H-indole)-3-carboxylate (QUPIC, 1) and quinolin-8-yl 1-(cyclohexylmethyl)-1H-indole-3-carboxylate (QUCHIC, 2); and two new cannabimimetic carboxamide derivatives, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (ADB-FUBINACA, 3) and N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indole-3-carboxamide (ADBICA, 4), as designer drugs in illegal products. Compound 3 was reported to have a potent affinity for cannabinoid CB1 receptor by Pfizer in 2009, but this is the first report of its detection in illegal products. No chemical or pharmacological data for compounds 1, 2, and 4 have appeared until now, making this the first report on these compounds. We also detected synthetic cannabinoids, APICA N-(5-fluoropentyl) analog (5), APINACA N-(5-fluoropentyl) analog (6), UR-144 N-(5-chloropentyl) analog (7), JWH-122 N-(5-chloropentyl) analog (8), and AM-2201 4-methoxynaphthyl analog (4-MeO-AM-2201, 9) herein as newly distributed designer drugs in Japan. It is of interest that compounds 1 and 2 were detected with their synthetic component, 8-quinolinol (10). A stimulant thiophene analog, α-pyrrolidinovalerothiophenone (α-PVT, 11), and an opioid receptor agonist, 3,4-dichloro-N-([1-(dimethylamino)cyclohexyl]methyl)benzamide (AH-7921, 12), were also detected as new types of designer drugs coexisting with several synthetic cannabinoids and cathinone derivatives in illegal products.

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[3.3.1.13,7]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.

Chemical analysis of a benzofuran derivative, 2-(2-ethylaminopropyl)benzofuran (2-EAPB), eight synthetic cannabinoids, five cathinone derivatives, and five other designer drugs newly detected in illegal products

From November 2013 to May 2014, 19 newly distributed designer drugs were identified in 104 products in our ongoing survey of illegal products in Japan. The identified compounds included 8 synthetic cannabinoids, FUB-PB-22 (1), 5-fluoro-NNEI indazole analog (5-fluoro-MN-18, 2), AM-2201 indazole analog (THJ-2201, 3), XLR-12 (4), 5-fluoro-AB-PINACA (5), 5-chloro-AB-PINACA (6), AB-CHMINACA (7), and 5-fluoro-AMB (8); 5 cathinone derivatives, DL-4662 (9), α-PHP (10), 4-methoxy-α-POP (11), 4-methoxy-α-PHPP (12), and 4-fluoro-α-PHPP (13); and 6 other substances, namely, the benzofuran derivative 2-(2-ethylaminopropyl)benzofuran (2-EAPB, 14), nitracaine (15), diclofensine (16), diphenidine (17), 1-benzylpiperidine (18), and acetylfentanyl (19). To our knowledge, this is the first report on the chemical properties of compounds 9–11 and 14. A total of 33 designer drugs, including compounds 1–19, were detected in the 104 illegal products, in 60 different combination patterns. The numbers of detected compounds per product ranged from 1 to 7. In addition, several products contained three different types of compounds, such as synthetic cannabinoids, cathinone derivatives, and phenethylamine derivatives per product. It is apparent that the types of compounds emerging as illegal products are becoming more diverse, as are their combinations.

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.

Erratum to: Two new synthetic cannabinoids, AM-2201 benzimidazole analog (FUBIMINA) and (4-methylpiperazin-1-yl)(1-pentyl-1H-indol-3-yl)methanone (MEPIRAPIM), and three phenethylamine derivatives, 25H-NBOMe 3,4,5-trimethoxybenzyl analog, 25B-NBOMe, and 2C-N-NBOMe, identified in illegal products

Two new types of synthetic cannabinoids, an AM-2201 benzimidazole analog (FUBIMINA, 1) and (4-methylpiperazin-1-yl)(1-pentyl-1H-indol-3-yl)methanone (MEPIRAPIM, 2), and three newly emerged phenethylamine derivatives, 25B-NBOMe (3), 2C-N-NBOMe (4), and a 25H-NBOMe 3,4,5-trimethoxybenzyl analog (5), were detected in illegal products distributed in Japan. The identification was based on liquid chromatography–mass spectrometry (LC–MS) and gas chromatography–mass spectrometry (GC–MS), high-resolution MS, and nuclear magnetic resonance analyses. Different from the representative synthetic cannabinoids, such as JWH-018, which have a naphthoylindole moiety, compounds 1 and 2 were completely new types of synthetic cannabinoids; compound 1 had a benzimidazole group in place of an indole group, and compound 2 had a 4-methylpiperazine group in place of the naphthyl group. Compounds 3 and 4 were N-o-methoxybenzyl derivatives of 2,5-dimethoxyphenethylamines (25-NBOMe series), which had been previously detected in European countries, but have newly emerged in Japan. Compound 5 had an N-trimethoxybenzyl group in place of an N-o-methoxybenzyl group. Data on the chemistry and pharmacology of compounds 1, 2, and 5 have never been reported to our knowledge.

A synthetic cannabinoid FDU-NNEI, two 2H-indazole isomers of synthetic cannabinoids AB-CHMINACA and NNEI indazole analog (MN-18), a phenethylamine derivative N-OH-EDMA, and a cathinone derivative dimethoxy-α-PHP, newly identified in illegal products

Six new psychoactive substances were identified together with two other substances (compounds 1–8) in illegal products by our ongoing survey in Japan between January and July 2014. A new synthetic cannabinoid, FDU-NNEI [1-(4-fluorobenzyl)-N-(naphthalen-1-yl)-1H-indole-3-carboxamide, 2], was detected with the newly distributed synthetic cannabinoid FDU-PB-22 (1). Two 2H-indazole isomers of synthetic cannabinoids, AB-CHMINACA 2H-indazole analog (3) and NNEI 2H-indazole analog (4), were newly identified with 1H-indazoles [AB-CHMINACA and NNEI indazole analog (MN-18)]. In addition, 2-methylpropyl N-(naphthalen-1-yl) carbamate (5) and isobutyl 1-pentyl-1H-indazole-3-carboxylate (6) were detected in illegal products. Compound 6 is considered to be a by-product of the preparation of NNEI indazole analog from compound 5 and 1-pentyl-1H-indazole. A phenethylamine derivative, N–OH-EDMA [N-hydroxy-3,4-ethylenedioxy-N-methylamphetamine, 7], and a cathinone derivative, dimethoxy-α-PHP (dimethoxy-α-pyrrolidinohexanophenone, 8), were newly identified in illegal products. Among them, compounds 1 and 8 have been controlled as designated substances (Shitei-Yakubutsu) under the Pharmaceutical Affairs Law in Japan since August and November 2014, respectively.

Antichagasic Activity of Komaroviquinone Is Due to Generation of Reactive Oxygen Species Catalyzed by Trypanosoma cruzi Old Yellow Enzyme

ABSTRACT A novel potent trypanocidal diterpene, komaroviquinone, was reduced by Trypanosoma cruzi old yellow enzyme (TcOYE) to its semiquinone radical. The reductase activity in trypanosome lysates was completely immunoabsorbed by anti-TcOYE antibody. Since TcOYE is expressed throughout the T. cruzi life cycle, komaroviquinone is an interesting candidate for developing new antichagasic drugs.

Identification of two new-type designer drugs, piperazine derivative MT-45 (I-C6) and synthetic peptide Noopept (GVS-111), with synthetic cannabinoid A-834735, cathinone derivative 4-methoxy-α-PVP, and phenethylamine derivative 4-methylbuphedrine from illegal products

We identified two new-type designer drugs, piperazine derivative MT-45 [1-cyclohexyl-4-(1,2-diphenylethyl)piperazine, synonym: I-C6, 1] and synthetic peptide Noopept [ethyl 2-(1-(2-phenylacetyl)pyrrolidine-2-carboxamido)acetate, synonym: GVS-111, 2], in chemical and herbal products. MT-45 (1) was previously reported as an opiate-like analgesic substance, and Noopept (2) was reported to have nootropic (cognitive enhancer) activity. We also detected two synthetic cannabinoids, A-834735 (3) and QUPIC N-(5-fluoropentyl) analog (synonym: 5-fluoro-PB-22, 4), in the illegal products. A-834735 (3) was previously reported to act as an agonist at both cannabinoid CB1 and CB2 receptors. In addition, cathinone derivative 4-methoxy-α-pyrrolidinovalerophenone (4-methoxy-α-PVP, 5) and phenethylamine derivative 4-methylbuphedrine (6) were newly detected with known cathinone derivative 4-methylbuphedrone (7) in the products.