Identification of a Cannabinoid Analog as a New Type of Designer Drug in a Herbal Product

Abstract

A new type of designer drug, a cannabinoid analog (1), was found in a herbal product distributed on the illegal drug market in Japan in expectation of its narcotic effect. The structure of 1 was identified by LC-MS, GC-MS, high-resolution MS, and NMR analyses. Compound 1 showed a molecular weight of 332, and accurate mass measurement exhibited its elemental composition to be C 22 H 36 O 2 . Together, the mass and NMR spectrometric data revealed that 1 was (1RS,3SR)-3-[4-(1,1-dimethyloctyl)-2-hydroxyphenyl]cyclohexan-1-ol, which was first synthesized in 1979 by a group at Pfizer Inc. and reported as a potent cannabinoid analog possessing cannabinoid receptor binding activity and analgesic activity in the 1990s. This is the first report to identify a cannabinoid analog in an illegal drug.Key words cannabinoid analog; designer drug; herbal product;Many types of chemicals are widely distributed and abused as psychotropic substances. In Japan every year this decade, a market survey of illegal drugs is performed by the Ministry of Health, Labour and Welfare. [1][2][3][4][5][6][7][8][9] Following the results of the survey, the compound identified and recognized as a designer drug [10][11][12] came to be strictly controlled by the Narcotics and Psychotropic Control Law or by the Pharmaceutical Affairs Law as designated substances (ShiteiYakubutsu). [13][14][15][16] In 2008, seven new designer drugs were classified as narcotics or designated substances, and all of them are analogs of phenylethylamine or tryptamine.Cannabis sativa L. (cannabis, hemp, marijuana, marihuana) is widely abused around the world because it contains psychoactive cannabinoids, such as D 9-tetrahydrocannabinol (D 9 -THC), which contains no amine groups (Fig. 1). In the past few decades, a number of analogs of D 9 -THC were synthesized, and their structure-activity relationships were studied. 17,18) In the 1980s, a group at Pfizer Inc. explored the development of analgesics using potent synthetic cannabinoids. [19][20][21][22] After the discovery of cannabinoid receptors, type 1 (CB 1, central type) and type 2 (CB 2 , peripheral type), as well as the discovery of an endogenous cannabinoid, their physiological roles were elucidated; a number of cannabinoid analogs were then newly synthesized, and their pharmacological activity for the treatment of various diseases was studied. 23,24) Recently, cannabis abuse seems to have spread in Japan. In this study, we identified a novel designer drug (1) possessing cannabinoid activity as an adulterant in a herbal product (Fig. 1). Compound 1 was first synthesized by Pfizer Inc. in 1979,25) and reported as a cannabinoid analog in the 1990s. [26][27][28][29][30] Although many designer drugs having phenylethylamine, tryptamine, and piperazine structures have been found, [10][11][12] this is the first report to identify a non-nitrogenated compound, a phenylcyclohexane derivative having cannabinoid activity. ExperimentalChemicals and Reagents HPLC-grade acetonitrile and all other chemicals (analytical grade) were ob...

Analytical characterization of some synthetic cannabinoids, derivatives of indole-3-carboxylic acid

“…Beginning in October 2012, new type of synthetic cannabinoids, a structural modification of compounds from 3-naphthoylindole series [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] has begun to be seized by police regularly, on the territory of Russia and Belarus.…”

Identification and analytical properties of new synthetic cannabimimetics bearing 2,2,3,3-tetramethylcyclopropanecarbonyl moiety

“…Numerous occurrences of these 'designer drugs' were detected in many countries including Russia and Belarus. These compounds are basically indole derivatives such as 3-naphthoylindoles, 3-phenylacetylindoles, 3-benzoylindoles and 3-adamantoylindoles [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

“…We have identified that since the summer 2011 most popular compounds, from the class, were: 'TMCP-018' (2), parent 3-(2,2,3,3-tetramethylcyclopropanecarbonyl)indole (1) and the other derivatives thereof (3)(4)(5)(6)(7), as well as {N-[3-(2-methoxyethyl)-4,5-dimethylthiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide} (8) ('A-836,339'), a thiazolidene analog of the compounds under discussion (Fig. 1).…”

Designer drugs: aspectos analíticos e biológicos

“…72 Esses compostos possuem estruturas químicas variadas, que vão desde derivados clássicos, que apresentam o anel dibenzopirano característico até estruturas não clássicas, derivadas do indol, indeno, pirrol, pirazol e cicloexanol, porém compartilhando a alta afinidade pelos receptores canabinoides. 18 As estruturas químicas de alguns derivados com ação canabinomimética estão representadas na Figura 7.…”

“…Para a detecção foram utilizadas a cromatografia líquida de ultra eficiência acoplada ao espectrômetro de massas (CLUE/ESI-EM) e detector de arranjo de diodos (CLUE/DAD), além de CG/EM. 18,72 Alguns derivados canabinoides foram analisados no sangue, utilizando CG/EM após extração em fase sólida e silanização. 74 Foi conduzido um estudo para a detecção de metabólitos de JWH-018 na urina, em que os metabólitos se conjugaram com ácido glicurônico e foram detectados por CG e CLAE/EM/EM.…”