Prediction of designer drugs: synthesis and spectroscopic analysis of synthetic cannabinoid analogues of 1H-indol-3-yl(2,2,3,3-tetramethylcyclopropyl)methanone and 1H-indol-3-yl(adamantan-1-yl)methanone

Drug Testing and Analysis

Volumn 8, Issue 10, 2016, Pages 1015-1029

  Carlsson, Andreas ^a   Lindberg, Sandra ^b   Wu, Xiongyu ^c   Dunne, Simon ^a   Josefsson, Martin ^c,d   Åstot, Crister ^b   Dahlén, Johan ^c  

^a National Forensic Centre   (Sweden)

^b SWEDISH DEFENCE RESEARCH AGENCY   (Sweden)

^c LINKÖPING UNIVERSITY   (Sweden)

^d National Board of Forensic Medicine   (Sweden)

Author keywords

drug analysis; mass spectrometry; proactive; synthesis; synthetic cannabinoids

Indexed keywords

COMMERCE; COPYRIGHTS; FOURIER TRANSFORM INFRARED SPECTROSCOPY; GASES; MASS SPECTROMETERS; NUCLEAR MAGNETIC RESONANCE; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; SPECTROSCOPIC ANALYSIS;

DESIGNER DRUGS; DRUG ANALYSIS; DRUG MARKETS; DRUG SYNTHESIS; FOURIER TRANSFORM INFRARED SPECTRA; GAS-PHASES; MASS SPECTRA; METHANONE; PROACTIVE; SYNTHETIC CANNABINOID;

MASS SPECTROMETRY;

(1 (2 (TETRAHYDRO 2H PYRAN 4 YL)ETHYL) 1H INDOL 3 YL)(2,2,3,3 TETRAMETHYLCYCLOPROPYL)METHANONE; (1 (4 FLUOROBUTYL) 1H INDOL 3 YL)(2,2,3,3 TETRAMETHYLCYCLOPROPYL)METHANONE; (1 BUTYL 1H INDOL 3 YL)(2,2,3,3 TETRAMETHYLCYCLOPROPYL)METHANONE; (1 BUTYL 1H INDOL 3 YL)(ADAMANTAN 1 YL)METHANONE; 1H INDOL 3 YL(2,2,3,3 TETRAMETHYLCYCLOPROPYL)METHANONE; 1H INDOL 3 YL(ADAMANTAN 1 YL)METHANONE; 2 (TETRAHYDRO 2H PYRAN 4 YL)ETHYL 4 METHYLBENZENESULFONATE; ADAMANTAN 1 YL(1H INDOL 3 YL)METHANONE; ADAMANTANE 1 CARBONYL CHLORIDE; CANNABINOID DERIVATIVE; DESIGNER DRUG; UNCLASSIFIED DRUG; 1H-INDOL-3-YL(2,2,3,3-TETRAMETHYLCYCLOPROPYL)METHANONE; 1H-INDOL-3-YL(ADAMANTAN-1-YL)METHANONE; CANNABINOID; INDOLE DERIVATIVE;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; ELECTROSPRAY MASS SPECTROMETRY; GAS CHROMATOGRAPHY; INFRARED SPECTROSCOPY; LIQUID CHROMATOGRAPHY; MASS FRAGMENTOGRAPHY; MASS SPECTROMETRY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PREDICTION; PRIORITY JOURNAL; SPECTROSCOPY; TIME OF FLIGHT MASS SPECTROMETRY; CHEMISTRY; SYNTHESIS;

CANNABINOIDS; DESIGNER DRUGS; GAS CHROMATOGRAPHY-MASS SPECTROMETRY; INDOLES; MAGNETIC RESONANCE SPECTROSCOPY; SPECTROSCOPY, FOURIER TRANSFORM INFRARED;

EID: 84949256916     PISSN: 19427603     EISSN: 19427611     Source Type: Journal    
DOI: 10.1002/dta.1904     Document Type: Article

References (62)

1. S. D. Brandt, L. A. King, M. Evans-Brown. The new drug phenomenon. Drug Test. Anal. 2014, 6, 587.
2. European monitoring centre for drugs and drug addiction. EMCDDA–Europol 2013 Annual report on the implementation of council decision 2005/387/JHA, Implementation reports, Publications office of the European Union, Luxembourg 2014.
3. United Nations Office on Drugs and Crime. World Drug Report. United Nations publication, Sales No. E.14.XI.7, 2014.
4. C. Rosenbaum, S. Carreiro, K. Babu. Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), Kratom, Salvia divinorum, methoxetamine, and piperazines. J. Med. Toxicol. 2012, 8, 15.
5. J. L. Wiley, J. A. Marusich, J. W. Huffman. Moving around the molecule: Relationship between chemical structure and in vivo activity of synthetic cannabinoids. Life Sci. 2014, 97, 55.
6. L. Fattore, W. Fratta. Beyond THC: the new generation of cannabinoid designer drugs. Front. Behav. Neurosci. 2011, 5.
7. D. Favretto, J. P. Pascali, F. Tagliaro. New challenges and innovation in forensic toxicology: Focus on the “New Psychoactive Substances”. J. Chromatogr. A. 2013, 1287, 84.
8. E. M. Gordon, R. W. Barrett, W. J. Dower, S. P. A. Fodor, M. A. Gallop. Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies, and future directions. J. Med. Chem. 1994, 37, 1385.
9. A. H. Lewin, H. H. Seltzman, F. I. Carroll, S. W. Mascarella, P. A. Reddy. Emergence and properties of spice and bath salts: A medicinal chemistry perspective. Life Sci. 2014, 97, 9.
10. R. S. Rapaka, V. Purohit, P. Schnur, J. Rutter. Emerging trends in the abuse of designer drugs and their catastrophic health effects: Update on chemistry, pharmacology, toxicology and addiction potential. Life Sci. 2014, 97, 1.
11. M. Mycyk. Emerging drugs of abuse: what was new yesterday is NEW today. J. Med. Toxicol. 2012, 8, 1.
12. D. Zuba, B. Byrska. Analysis of the prevalence and coexistence of synthetic cannabinoids in “herbal high” products in Poland. Forensic Toxicol. 2013, 31, 21.
13. N. Uchiyama, M. Kawamura, R. Kikura-Hanajiri, Y. Goda. 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. Forensic Toxicol. 2012, 30, 114.
14. V. Koller, G. Zlabinger, V. Auwärter, S. Fuchs, S. Knasmueller. Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB1. Arch. Toxicol. 2013, 87, 1287.
15. A. B. Schneir, J. Cullen, B. T. Ly. 'Spice' girls: Synthetic cannabinoid intoxication. J. Emerg. Med. 2011, 40, 296.
16. M. Cole. Poison in party pills is too much to swallow. Nature. 2011, 474. DOI: 10.1038/474253a
17. J. Lapoint, L. P. James, C. L. Moran, L. S. Nelson, R. S. Hoffman, J. H. Moran. Severe toxicity following synthetic cannabinoid ingestion. Clin. Toxicol. 2011, 49, 760.
18. I. Ojanperä, M. Gergov, M. Liiv, A. Riikoja, E. Vuori. An epidemic of fatal 3-methylfentanyl poisoning in Estonia. J. Leg. Med. 2008, 122, 395.
19. B. Murray, C. Murphy, M. Beuhler. Death following recreational use of designer drug “bath salts” containing 3,4-methylenedioxypyrovalerone (MDPV). J. Med. Toxicol. 2012, 8, 69.
20. L. Yip, R. Dart. Is there something more about synthetic cannabinoids? Forensic Toxicol. 2014, 1.
21. V. Khullar, A. Jain, M. Sattari. Emergence of new classes of recreational drugs—Synthetic cannabinoids and cathinones. J. Gen. Intern. Med. 2014, 1.
22. C. S. Berry-Cabán, J. Ee, V. Ingram, C. E. Berry, E. H. Kim. Synthetic cannabinoid overdose in a 20-year-old male US soldier. Subst. Abuse. 2012, 34, 70.
23. L. Ernst, H.-M. Schiebel, C. Theuring, R. Lindigkeit, T. Beuerle. Identification and characterization of JWH-122 used as new ingredient in “Spice-like” herbal incenses. Forensic Sci. Int. 2011, 208, e31.
24. M. E. Nelson, S. M. Bryant, S. E. Aks. Emerging drugs of abuse. Disease-a-month: DM. 2014, 60, 110.
25. S. L. Hill, S. H. L. Thomas. Clinical toxicology of newer recreational drugs. Clin. Toxicol. 2011, 49, 705.
26. P. Deluca, Z. Davey, O. Corazza, L. Di Furia, M. Farre, L. H. Flesland, M. Mannonen, A. Majava, T. Peltoniemi, M. Pasinetti, C. Pezzolesi, N. Scherbaum, H. Siemann, A. Skutle, M. Torrens, P. van der Kreeft, E. Iversen, F. Schifano. Identifying emerging trends in recreational drug use; outcomes from the Psychonaut Web Mapping Project. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2012, 39, 221.
27. R. Kikura-Hanajiri, N. Uchiyama, M. Kawamura, Y. Goda. Changes in the prevalence of synthetic cannabinoids and cathinone derivatives in Japan until early 2012. Forensic Toxicol. 2013, 31, 44.
28. H. Chung, H. Choi, S. Heo, E. Kim, J. Lee. Synthetic cannabinoids abused in South Korea: drug identifications by the National Forensic Service from 2009 to June 2013. Forensic Toxicol. 2014, 32, 82.
29. S. Assi, S. Fergus, J. Stair, O. Corazza, F. Schifano. Emergence and identification of new products of designer drug products from the Internet. European Pharmaceutical Review. 2011, 4, 68.
30. N. Langer, R. Lindigkeit, H.-M. Schiebel, L. Ernst, T. Beuerle. Identification and quantification of synthetic cannabinoids in ‘spice-like’ herbal mixtures: A snapshot of the German situation in the autumn of 2012. Drug Test. Anal. 2014, 6, 59.
31. R. Kronstrand, M. Roman, M. Andersson, A. Eklund. Toxicological Findings of synthetic cannabinoids in recreational users. J. Anal. Toxicol. 2013, 37, 534.
32. A. Helander, M. Bäckberg, P. Hultén, Y. Al-Saffar, O. Beck. Detection of new psychoactive substance use among emergency room patients: Results from the Swedish STRIDA project. Forensic Sci. Int. 2014, 243, 23.
33. V. Auwärter, S. Dresen, W. Weinmann, M. Müller, M. Pütz, N. Ferreirós. ‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs? J. Mass Spectrom. 2009, 44, 832.
34. N. Uchiyama, R. Kikura-Hanajiri, N. Kawahara, Y. Haishima, Y. Goda. Identification of a cannabinoid analog as a new type of designer drug in a herbal product. Chem. Pharm. Bull. (Tokyo). 2009, 57, 439.
35. S. Dresen, N. Ferreirós, M. Pütz, F. Westphal, R. Zimmermann, V. Auwärter. Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. J. Mass Spectrom. 2010, 45, 1186.
36. Commission decision implementing Council Directive. 96/23/EC concerning the performance of analytical methods and the interpretation of results (2002/657/EC). Official Journal of the European Communities. 2002 L 221, 17/08/2002 P. 0008.
37. S. Laks, A. Pelander, E. Vuori, E. Ali-Tolppa, E. Sippola, I. Ojanperä. Analysis of street drugs in seized material without primary reference standards. Anal. Chem. 2004, 76, 7375.
38. UNODC. Recommended Methods for the Identification and Analysis of Synthetic Cannabinoid Receptor Agonists in Seized Materials. United Nations: New York, 2013.
39. R. A. Musah, M. A. Domin, R. B. Cody, A. D. Lesiak, A. John Dane, J. R. E. Shepard. Direct analysis in real time mass spectrometry with collision-induced dissociation for structural analysis of synthetic cannabinoids. Rapid Commun. Mass Spectrom. 2012, 26, 2335.
40. M. Praisler, I. Dirinck, J. Van Bocxlaer, A. De Leenheer, D. L. Massart. Identification of novel illicit amphetamines from vapor-phase FTIR spectra — a chemometrical solution. Talanta. 2000, 53, 155.
41. S. Gosav, R. Dinica, M. Praisler. Choosing between GC–FTIR and GC–MS spectra for an efficient intelligent identification of illicit amphetamines. J. Mol. Struct. 2008, 887, 269.
42. K. G. Shanks, T. Dahn, G. Behonick, A. Terrell. Analysis of first and second generation legal highs for synthetic cannabinoids and synthetic stimulants by ultra-performance liquid chromatography and time of flight mass spectrometry. J. Anal. Toxicol. 2012, 36, 360.
43. R. Kronstrand, L. Brinkhagen, C. Birath-Karlsson, M. Roman, M. Josefsson. LC-QTOF-MS as a superior strategy to immunoassay for the comprehensive analysis of synthetic cannabinoids in urine. Anal. Bioanal. Chem. 2014, 406, 3599.
44. H. Bergkvist, J. Eyem, L. Lundberg. Fast automatic identification of drugs of abuse by means of combined gas chromatography-fourier transform infrared spectroscopy (GC-FTIR). Thirteenth international symposium on capillary chromatography. Riva del Garda, Italy, 1991, p. 1160.
45. M. A. ElSohly, W. Gul, A. S. Wanas, M. M. Radwan. Synthetic cannabinoids: Analysis and metabolites. Life Sci. 2014, 97, 78.
46. B. Moosmann, S. Kneisel, U. Girreser, V. Brecht, F. Westphal, V. Auwärter. Separation and structural characterization of the synthetic cannabinoids JWH-412 and 1-[(5-fluoropentyl)-1H-indol-3-yl]-(4-methylnaphthalen-1-yl)methanone using GC-MS, NMR analysis and a flash chromatography system. Forensic Sci. Int. 2012, 220, e17.
47. D. Zuba, B. Geppert, K. Sekuła, C. Żaba. [1-(Tetrahydropyran-4-ylmethyl)-1H-indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl)methanone: a new synthetic cannabinoid identified on the drug market. Forensic Toxicol. 2013, 31, 281.
48. P. Jankovics, A. Váradi, L. Tölgyesi, S. Lohner, J. Németh-Palotás, H. Kőszegi-Szalai. Identification and characterization of the new designer drug 4′-methylethcathinone (4-MEC) and elaboration of a novel liquid chromatography–tandem mass spectrometry (LC–MS/MS) screening method for seven different methcathinone analogs. Forensic Sci. Int. 2011, 210, 213.
49. J. I. Nakajima, M. Takahashi, R. Nonaka, T. Seto, J. Suzuki, M. Yoshida, C. Kanai, T. Hamano. Identification and quantitation of a benzoylindole (2-methoxyphenyl)(1-pentyl-1H-indol-3-yl) methanone and a naphthoylindole 1-(5-fluoropentyl-1H-indol-3-yl)-(naphthalene-1-yl) methanone (AM-2201) found in illegal products obtained via the Internet and their cannabimimetic effects evaluated by in vitro [35S] GTPγS binding assays. Forensic Toxicol. 2011, 29, 132.
50. J. I. Nakajima, M. Takahashi, T. Seto, M. Yoshida, C. Kanai, J. Suzuki, T. Hamano. Identification and quantitation of two new naphthoylindole drugs-of-abuse, (1-(5-hydroxypentyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (AM-2202) and (1-(4-pentenyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone, with other synthetic cannabinoids in unregulated 'herbal' products circulated in the Tokyo area. Forensic Toxicol. 2012, 30, 33.
51. B. K. Logan, L. E. Reinhold, A. Xu, F. X. Diamond. Identification of synthetic cannabinoids in herbal incense blends in the United States. J. Forensic Sci. 2012, 57, 1168.
52. S. Beuck, I. Moller, A. Thomas, A. Klose, N. Schlorer, W. Schanzer, M. Thevis. Structure characterisation of urinary metabolites of the cannabimimetic JWH-018 using chemically synthesised reference material for the support of LC-MS/MS-based drug testing. Anal. Bioanal. Chem. 2011, 401, 493.
53. J. M. Frost, M. J. Dart, K. R. Tietje, T. R. Garrison, G. K. Grayson, A. V. Daza, O. F. El-Kouhen, B. B. Yao, G. C. Hsieh, M. Pai, C. Z. Zhu, P. Chandran, M. D. Meyer. Indol-3-ylcycloalkyl ketones: Effects of N1 substituted indole side chain variations on CB2 cannabinoid receptor activity. J. Med. Chem. 2010, 53, 295.
54. S. D. Banister, J. Stuart, R. C. Kevin, A. Edington, M. Longworth, S. M. Wilkinson, C. Beinat, A. S. Buchanan, D. E. Hibbs, M. Glass, M. Connor, I. S. McGregor, M. Kassiou. Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135. ACS Chemical Neuroscience. 2015, 6, 1445.
55. N. Uchiyama, M. Kawamura, R. Kikura-Hanajiri, Y. Goda. URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products. Forensic Sci. Int. 2013, 227, 21.
56. V. Shevyrin, V. Melkozerov, A. Nevero, O. Eltsov, Y. Morzherin, Y. Shafran. Identification and analytical properties of new synthetic cannabimimetics bearing 2,2,3,3-tetramethylcyclopropanecarbonyl moiety. Forensic Sci. Int. 2013, 226, 62.
57. H. Choi, S. Heo, E. Kim, B. Y. Hwang, C. Lee, J. Lee. 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. Forensic Toxicol. 2013, 31, 86.
58. J. M. Frost, M. J. Dart, K. R. Tietje, T. R. Garrison, G. K. Grayson, A. V. Daza, O. F. El-Kouhen, L. N. Miller, L. Li, B. B. Yao, G. C. Hsieh, M. Pai, C. Z. Zhu, P. Chandran, M. D. Meyer. Indol-3-yl-tetramethylcyclopropyl ketones: Effects of indole ring substitution on CB2 cannabinoid receptor activity. J. Med. Chem. 2008, 51, 1904.
59. P. Jankovics, A. Váradi, L. Tölgyesi, S. Lohner, J. Németh-Palotás, J. Balla. Detection and identification of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3-(1-adamantoyl)indole in seized bulk powders in Hungary. Forensic Sci. Int. 2012, 214, 27.
60. S. Kneisel, F. Westphal, P. Bisel, V. Brecht, S. Broecker, V. Auwärter. Identification and structural characterization of the synthetic cannabinoid 3-(1-adamantoyl)-1-pentylindole as an additive in ‘herbal incense’. J. Mass Spectrom. 2012, 47, 195.
61. S. D. Banister, S. M. Wilkinson, M. Longworth, J. Stuart, N. Apetz, K. English, L. Brooker, C. Goebel, D. E. Hibbs, M. Glass, M. Connor, I. S. McGregor, M. Kassiou. The synthesis and pharmacological evaluation of adamantane-derived indoles: Cannabimimetic drugs of abuse. ACS Chemical Neuroscience. 2013, 4, 1081.
62. A. Grigoryev, P. Kavanagh, A. Melnik, S. Savchuk, A. Simonov. Gas and liquid chromatography-mass spectrometry detection of the urinary metabolites of UR-144 and its major pyrolysis product. J. Anal. Toxicol. 2013, 37, 265.