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Chemistry, Pharmacology, and Metabolism of Emerging Drugs of Abuse

Maurer, Hans H PhD

doi: 10.1097/FTD.0b013e3181eea318
Review Article
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In recent years, besides the classic designer drugs of the amphetamine type, a series of new drug classes appeared on the illicit drugs market. The chemistry, pharmacology, toxicology, metabolism, and toxicokinetics is discussed of 2,5-dimethoxy amphetamines, 2,5-dimethoxy phenethylamines, beta-keto-amphetamines, phencyclidine derivatives as well as of herbal drugs, ie, Kratom. They have gained popularity and notoriety as rave drugs. The metabolic pathways, the involvement of cytochrome P450 isoenzymes in the main pathways, and their roles in hepatic clearance are also summarized.

From the Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg (Saar), Germany.

Received for publication January 27, 2010; accepted February 20, 2010.

Correspondence: Hans H. Maurer, PhD, Department of Experimental and Clinical Toxicology, Saarland University, D-66421 Homburg (Saar), Germany (e-mail: hans.maurer@uks.eu).

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INTRODUCTION

In recent years, besides the classic designer drugs of the amphetamine-type,1-11 a series of new drug classes appeared on the illicit drugs market such as 4-substituted or 2,5-dimethoxy amphetamines,12-17 2,5-phenethylamines (2Cs),18-23 beta-keto-amphetamines,24,25 and phencyclidine derivatives.26-29 Piperazines and pyrrolidinophenones have already been reviewed.1,30-32 Although designer drugs have the reputation of being safe, several experimental studies in rats and humans and epidemiologic studies indicated risks to humans including a life-threatening serotonin syndrome, hepatotoxicity, neurotoxicity, psychopathology, and abuse potential.1,9,12,33-37 In recent years, new herbal drugs also appeared on the drug scene such as Kratom38,39 and Spice.40,41 The latter, however, was fortified by synthetic cannabinoids receptor agonists for which metabolic data have not yet been published. Because metabolites were suspected to contribute to some of the toxic effects3,34,42 and their knowledge is of importance for developing screening approaches, the main metabolic steps are also described. More detailed reviews will be published elsewhere.43 Procedures for toxicologic analysis of emerging drugs of abuse are discussed by Peters and Martinez-Ramirez elsewhere.44

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2,5-DIMETHOXY AMPHETAMINE DESIGNER DRUGS

Typical drugs of this class are 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-chloro-2,5-dimethoxyamphetamine (DOC), 4-iodo-2,5-dimethoxyamphetamine (DOI), 2,5-dimethoxy-4-methyl-amphetamine (DOM), 4-bromo-2,5-dimethoxymethamphetamine (MDOB), and 2,4,5-trimethoxyamphetamine (TMA-2). Their chemical structures are shown in Figure 1. Most of these drugs were described by Shulgin.45 They were sold in so-called “smart shops” alone or in mixtures with other designer drugs in the form of tablets, powder, liquids, or blotters. This trend was accompanied by seizures by the police of tablets containing 2,5-dimethoxyamphetamines or combinations with other drugs. Because of the high abuse potential of the 2,5-dimethoxyamphetamines, many were scheduled in most countries. Some information is available on pharmacologic properties of the 2,5-dimethoxyamphetamines. They show affinity to 5-HT2 receptors and act as agonists or antagonists at different receptor subtypes.46-51 Because of the high potency and selectivity of DOI as a 5-HT2 receptor agonist and the fact that it was not scheduled until now and is commercially available, it was used in research when a selective 5-HT2 receptor agonist was needed.52,53 The chemical structure responsible for the hallucinogen-like activity comprises a primary amine functionality separated from the phenyl ring by two carbon atoms, the presence of methoxy groups in positions 2 and 5 of the aromatic ring, and a hydrophobic 4-substituent (alkyl, halogen, alkylthio, etc).51 The methyl moiety in α-position to the nitrogen atom is reported to be responsible for increased in vivo potency and duration of action.51 The metabolism of these drugs has been studied in detail.13-17,54-56 Although for all of these drugs, demethylation of one of the 2,5 methoxy groups by cytochrome P450 (CYP) 2D6 was observed, these drugs were found to be more or less potent CYP2D6 inhibitors.54

FIGURE 1

FIGURE 1

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2,5-DIMETHOXY PHENETHYLAMINE DESIGNER DRUGS

2,5-Dimethoxy phenethylamines, the so-called 2Cs, are analogs of the previously mentioned 2,5-dimethoxyamphetamines (phenylisopropylamines). The chemical structures of the 2Cs 4-bromo-2,5-dimethoxy-β-phenethylamine (2C-B), 4-iodo-2,5-dimethoxy-β-phenethylamine (2C-I), 2,5-dimethoxy-4-methyl-β-phenethylamine (2C-D), 4-ethyl-2,5-dimethoxy-β-phenethylamine (2C-E), 4-ethylthio-2,5-dimethoxy-β-phenethylamine (2C-T-2), and 2,5-dimethoxy-4-propylthio-β-phenethylamine (2C-T-7) are shown in Figure 2. Again, they were described by Shulgin.45

FIGURE 2

FIGURE 2

Only little information is available on pharmacologic and toxicologic properties of the members of the 2C series, but it is known that they show affinity to 5-HT2 receptors and act as agonists or antagonists at different receptor subtypes.45,50,51,57-60 For 2C-B, partial agonism at α1-adrenergic receptors was described.61,62 Because of these properties, radioactive 2C-I was synthesized as a label for the 5-HT2 receptor and as a potential brain scanning agent for nuclear medicine.57,63 The chemical structure responsible for the hallucinogen-like activity comprises a primary amine functionality separated from the phenyl ring by two carbon atoms (“2C”), the presence of methoxy groups in positions 2 and 5 of the aromatic ring, and a hydrophobic 4-substituent (alkyl, halogen, alkylthio, etc).51 Furthermore, several quantitative structure-activity relationships studies were published about hallucinogenic β-phenethylamines.64-71 Using the results of these analyses, predictions of the hallucinogenic potency of new β-phenethylamines should be possible.

The 2Cs were mainly metabolized by O-demethylation in positions 2 and 5 of the ring, respectively, by deamination followed by oxidation to the corresponding acid or reduction to the corresponding alcohol. Further metabolic steps were side chain hydroxylation and in the case of sulfur containing 2Cs, sulfoxidation. Metabolic Phase II reactions were partial glucuronidation or sulfation and N-acetylation. Combinations of these steps and minor metabolites could also be detected.18-23,72-80 MAO-A and MAO-B were the major enzymes involved in the deamination reaction.80 For 2C-D, 2C-E, 2C-T-2, and 2C-T-7, CYP2D6 was also involved, but only to a small extent. All studied 2Cs have a slightly higher affinity for MAO-A than for MAO-B, which can be explained by the size of the binding pocket of the enzyme for the 4-substituent of the 2Cs.80

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BETA-KETO-AMPHETAMINE DESIGNER DRUGS

The beta-keto (bk) designer drugs butylone (2-methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one, bk-MBDB), ethylone (3,4-methylenedioxyethylcathinone, bk-3,4-methylenedioxyethylamphetamine, bk-MDEA), methylone (3,4-methylenedioxymethcathinone, bk-3,4-methylenedioxymethamphetamine, bk-MDMA), and mephedrone (2-methylamino-1-p-tolylpropane-1-one, bk-4-methylmethamphetamine) belong to a new class of drugs of abuse. Their chemical structures are shown in Figure 3.

FIGURE 3

FIGURE 3

Although no data exist on their pharmacologic and toxicologic properties, their use as alternative drugs for amphetamines allows to conclude that they should have similar stimulant effects. The bk designer drugs were metabolized by humans in analogy to corresponding amphetamines and additionally reduced at the beta-keto group to the corresponding alcohol. bk-MBDB, bk-MDEA, and bk-MDMA are mainly demethylenated and subsequently O-methylated as well as N-dealkylated and finally, the keto groups reduced.24,25 Mephedrone was hydroxylated at the 4-methyl group followed by oxidation to the corresponding 4-carboxy metabolite, N-demethylated finally reduced at the beta-keto group to the corresponding alcohol.81

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PHENCYCLIDINE-DERIVED DESIGNER DRUGS

Several phencyclidine (PCP)-derived designer drugs were seized in Germany, namely, N-(1-phenylcyclohexyl)-propanamine (PCPr), N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA), N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA), and N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA).82 In expectance of its appearance on the illicit drug market, a further homolog, namely, N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA), was synthesized as a reference substance for scientific purposes. Chemical structures of these compounds are shown in Figure 4.

FIGURE 4

FIGURE 4

Unfortunately, only little information on the pharmacologic properties of these compounds is available.83 As a result of structural similarities, they might be assumed to be similar to those of PCP or ketamine, which both act as antagonists at N-methyl-D-aspartate (NMDA) receptors and have psychotomimetic as well as anesthetic properties.84 Furthermore, it has been reported that (1-phenylcyclohexyl)-amine, a known metabolite of PCP and of the previously mentioned PCP-derived compounds,26-29 produced a long-lasting dose-dependent effect on the efflux of dopamine in the rat.85 A similar pharmacologic profile of the mentioned PCP-derived compounds would clearly be in line with their abuse as designer drugs.

These phencyclidine-derived compounds were mainly metabolized by O-dealkylation, followed by oxidation to the corresponding acid, hydroxylation of the cyclohexyl ring in different positions, hydroxylation of the phenyl ring, N-dealkylation, and combinations of these steps. Phase II reactions consisted of partial glucuronidation and/or sulfation of some Phase I metabolites.26-29 The main metabolic step of PCEPA, PCMPA, PCEEA, and PCMEA was catalyzed by different CYP isoforms.86,87

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HERBAL DRUG KRATOM

The plant Mitragyna speciosa Korth. (Rubiaceae) is native in Thailand and other southeast Asian countries and its Thai name is “Kratom.” 88,89 The leaves of Mitragyna speciosa have been used in Thailand for its opium-like effect and its coca-like ability to combat fatigue of and enhance tolerance to hard workers under a scoring sun.90 In addition, it has been used as a traditional medicine for common illnesses such as coughing, diarrhea, muscle pain, hypertension, and to cure morphine addicts.91,92 The main alkaloids are mitragynine (MG, approximately 60% based on the crude base), paynantheine (PAY, approximately 10%), and speciogynine (SP, 5%-10%).93 Chemical structures of these compounds are shown in Figure 5. Because of its stimulant and euphoric effects, Kratom is misused as an herbal drug of abuse, which has been illegal in Thailand since 1946 and in Australia since 2005. The wide availability of Kratom through the Internet reflects extensive demand for this product. For example, opiate addicts may attempt to mitigate opioid withdrawal symptoms.94

FIGURE 5

FIGURE 5

The Phase I and II metabolism of MG and PAY in rats and humans was extensively studied using liquid chromatography-mass spectrometry with a linear ion trap analyzer providing detailed structure information in the MSn mode and using high-resolution mass spectrometry with an Orbitrap analyzer providing the empiric formula of the corresponding fragments for confirmation.38,39 MG and PAY were metabolized by hydrolysis of the methylester in position 16, O-demethylation of the 9-methoxy group and of the 17-methoxy group, followed, through the corresponding aldehydes, by oxidation to carboxylic acids or reduction to alcohols and combinations of some steps. In rats, four metabolites were additionally conjugated to glucuronides and one to sulfate, but in humans, three metabolites to glucuronides and three to sulfates.

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CONCLUSIONS

The drugs of abuse market is dynamic with new drugs always appearing. Toxicologists must follow up these trends and have to investigate the chemical, analytical, toxicologic, and metabolic properties of these emerging drugs. Finally, clinical case data are necessary to assess the impact of these drugs to human health.

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ACKNOWLEDGMENT

I thank Dr. Markus R. Meyer for his support.

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REFERENCES

1. Maurer HH, Kraemer T, Springer D, et al. Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of the amphetamine (ecstasy), piperazine, and pyrrolidinophenone types, a synopsis. Ther Drug Monit. 2004;26:127-131.
2. de la Torre R, Farre M, Roset PN, et al. Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit. 2004;26:137-144.
3. Kraemer T, Maurer HH. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, of amphetamine, methamphetamine and their N-alkyl derivatives. Ther Drug Monit. 2002;24:277-289.
4. Meyer MR, Peters FT, Maurer HH. The role of human hepatic cytochrome P450 isozymes in the metabolism of racemic 3,4-methylenedioxy-methamphetamine and its enantiomers. Drug Metab Dispos. 2008;36:2345-2354.
5. Meyer MR, Peters FT, Maurer HH. Investigations on the human hepatic cytochrome P450 isozymes involved in the metabolism of 3,4-methylenedioxy-amphetamine (MDA) and benzodioxolyl-butanamine (BDB) enantiomers. Toxicol Lett. 2009;190:54-60.
6. Meyer MR, Peters FT, Maurer HH. Stereoselective differences in the cytochrome P450-dependent dealkylation and demethylenation of N-methyl-benzodioxolyl-butanamine (MBDB, Eden) enantiomers. Biochem Pharmacol. 2009;77:1725-1734.
7. Meyer MR, Peters FT, Maurer HH. The role of human hepatic cytochrome P450 isozymes in the metabolism of racemic 3,4-methylenedioxyethylamphetamine and its single enantiomers. Drug Metab Dispos. 2009;37:1152-1156.
8. Meyer MR, Maurer HH. Enantioselectivity in the methylation of the catecholic phase-I metabolites of methylenedioxy designer drugs and their capability to inhibit COMT catalyzed dopamine 3-methylation. Chem Res Toxicol. 2009;22:1205-1211.
9. Mueller M, Yuan J, Felim A, et al. Further studies on the role of metabolites in MDMA-induced serotonergic neurotoxicity. Drug Metab Dispos. 2009;37:2079-2086.
10. Schwaninger AE, Meyer MR, Zapp J, et al. The role of human UDP-glucuronyltransferases on the formation of the methylenedioxymethamphetamine (ecstasy) phase I metabolites R- and S-3-methoxymethamphetamine 4-O-glucuronides. Drug Metabol Dispos. 2009;37:2212-2220.
11. Shima N, Katagi M, Kamata H, et al. Urinary excretion of the main metabolites of 3,4-methylenedioxymethamphetamine (MDMA), including the sulfate and glucuronide of 4-hydroxy-3-methoxymethamphetamine (HMMA), in humans and rats. Xenobiotica. 2008;38:314-324.
12. Balikova M. Nonfatal and fatal DOB (2,5-dimethoxy-4-bromoamphetamine) overdose. Forensic Sci Int. 2005;153:85-91.
13. Ewald AH, Fritschi G, Bork WR, et al. Designer drugs 2,5-dimethoxy-4-bromoamphetamine (DOB) and 2,5-dimethoxy-4-bromomethamphetamine (MDOB): studies on their metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques. J Mass Spectrom. 2006;41:487-498.
14. Ewald AH, Fritschi G, Maurer HH. Designer drug 2,4,5-trimethoxyamphetamine (TMA-2): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques. J Mass Spectrom. 2006;41:1140-1148.
15. Ewald AH, Fritschi G, Maurer HH. Metabolism and toxicological detection of the designer drug 4-iodo-2,5-dimethoxy-amphetamine (DOI) in rat urine using gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;857:170-174.
16. Ewald AH, Puetz M, Maurer HH. Designer drug 2,5-dimethoxy-4-methyl-amphetamine (DOM, STP): Involvement of the cytochrome P450 isoenzymes in formation of its main metabolite and detection of the latter in rat urine as proof of a drug intake using gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;862:252-256.
17. Ewald AH, Ehlers D, Maurer HH. Metabolism and toxicological detection of the designer drug 4-chloro-2,5-dimethoxyamphetamine in rat urine using gas chromatography-mass spectrometry. Anal Bioanal Chem. 2008;390:1837-1842.
18. Theobald DS, Staack RF, Puetz M, et al. New designer drug 2,5-dimethoxy-4-ethylthio-beta-phenethylamine (2C-T-2): studies on its metabolism and toxicological detection in rat urine using gas chromatography/mass spectrometry. J Mass Spectrom. 2005;40:1157-1172.
19. Theobald DS, Fehn S, Maurer HH. New designer drug 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7): studies on its metabolism and toxicological detection in rat urine using gas chromatography/mass spectrometry. J Mass Spectrom. 2005;40:105-116.
20. Theobald DS, Maurer HH. Studies on the metabolism and toxicological detection of the designer drug 4-ethyl-2,5-dimethoxy-beta-phenethylamine (2C-E) in rat urine using gas chromatographic-mass spectrometric techniques. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;842:76-90.
21. Theobald DS, Maurer HH. Studies on the metabolism and toxicological detection of the designer drug 2,5-dimethoxy-4-methyl-beta-phenethylamine (2C-D) in rat urine using gas chromatographic-mass spectrometric techniques. J Mass Spectrom. 2006;41:1509-1519.
22. Theobald DS, Putz M, Schneider E, et al. New designer drug 4-iodo-2,5-dimethoxy-beta-phenethylamine (2C-I): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric and capillary electrophoretic/mass spectrometric techniques. J Mass Spectrom. 2006;41:872-886.
23. Theobald DS, Fritschi G, Maurer HH. Studies on the toxicological detection of the designer drug 4-bromo-2,5-dimethoxy-beta-phenethylamine (2C-B) in rat urine using gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;846:374-377.
24. Kamata HT, Shima N, Zaitsu K, et al. Metabolism of the recently encountered designer drug, methylone, in humans and rats. Xenobiotica. 2006;36:709-723.
25. Zaitsu K, Katagi M, Kamata HT, et al. Determination of the metabolites of the new designer drugs bk-MBDB and bk-MDEA in human urine. Forensic Sci Int. 2009;188:131-139.
26. Sauer C, Peters FT, Staack RF, et al. New designer drug 1-(1-phenylcyclohexyl)-3-ethoxypropylamine (PCEPA): Studies on its metabolism and toxicological detection in rat urine using gas chromatography/mass spectrometry. J Mass Spectrom. 2006;41:1014-1029.
27. Sauer C, Peters FT, Staack RF, et al. New designer drugs N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA) and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA): Studies on their metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques. J Mass Spectrom. 2008;43:305-316.
28. Sauer C, Peters FT, Staack RF, et al. Metabolism and toxicological detection of a new designer drug, N-(1-phenylcyclohexyl)propanamine, in rat urine using gas chromatography-mass spectrometry. J Chromatogr A. 2008;1186:380-390.
29. Sauer C, Peters FT, Staack RF, et al. Metabolism and toxicological detection of the designer drug N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA) in rat urine using gas chromatography-mass spectrometry. Forensic Sci Int. 2008;181:47-51.
30. Staack RF, Maurer HH. Metabolism of designer drugs of abuse. Curr Drug Metab. 2005;6:259-274.
31. Peters FT, Meyer MR, Fritschi G, et al. Studies on the metabolism and toxicological detection of the new designer drug 4'-methyl-alpha-pyrrolidinobutyrophenone (MPBP) in urine using gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;824:81-91.
32. Sauer C, Peters FT, Haas C, et al. New designer drug alpha-pyrrolidinovalerophenone (PVP): Studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques. J Mass Spectrom. 2009;44:952-964.
33. Antia U, Tingle MD, Russell BR. Metabolic interactions with piperazine-based ‘party pill' drugs. J Pharm Pharmacol. 2009;61:877-882.
34. Nakagawa Y, Suzuki T, Tayama S, et al. Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its analogues, on isolated rat hepatocytes. Arch Toxicol. 2009;83:69-80.
35. Austin H, Monasterio E. Acute psychosis following ingestion of ‘Rapture.' Australas Psychiatry. 2004;12:406-408.
36. Kalant H. The pharmacology and toxicology of ‘ecstasy' (MDMA) and related drugs. Can Med Assoc J. 2001;165:917-928.
37. Wood DM, Dargan PI, Button J, et al. Collapse, reported seizure-and an unexpected pill. Lancet. 2007;369:1490.
38. Philipp AA, Wissenbach DK, Zoerntlein SW, et al. Studies on the metabolism of mitragynine, the main alkaloid of the herbal drug Kratom, in rat and human urine using liquid chromatography-linear ion trap mass spectrometry. J Mass Spectrom. 2009;44:1249-1261.
39. Philipp AA, Wissenbach DK, Weber AA, et al. Use of liquid chromatography coupled to low and high resolution linear ion trap mass spectrometry for studying the metabolism of paynantheine, an alkaloid of the herbal drug Kratom in rat and human urine. Anal Bioanal Chem. 2010;396:2379-2391.
40. Auwarter V, Dresen S, Weinmann W, et al. ‘Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? J Mass Spectrom. 2009;44:832-837.
41. Lindigkeit R, Boehme A, Eiserloh I, et al. Spice: a never ending story? Forensic Sci Int. 2009;191:58-63.
42. Hiramatsu M, Kumagai Y, Unger SE, et al. Metabolism of methylenedioxymethamphetamine: formation of dihydroxymethamphetamine and a quinone identified as its glutathione adduct. J Pharmacol Exp Ther. 1990;254:521-527.
43. Meyer MR, Maurer HH. Metabolism of designer drugs of abuse-an update. Curr Drug Metab. 2010;11:468-482.
44. Peters FT, Martinez-Ramirez JA. Analytical toxicology of emerging drugs of abuse. Ther Drug Monit. 2010;32:532-539.
45. Shulgin A. Pihkal, a Chemical Love Story, 1st ed. Berkley, CA: Transform Press; 1991.
46. Acuna-Castillo C, Villalobos C, Moya PR, et al. Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors. Br J Pharmacol. 2002;136:510-519.
47. Glennon RA, Titeler M, McKenney JD. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci. 1984;35:2505-2511.
48. Glennon RA, McKenney JD, Lyon RA, et al. 5-HT1 and 5-HT2 binding characteristics of 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane analogues. J Med Chem. 1986;29:194-199.
49. Glennon RA, Titeler M, Seggel MR, et al. N-methyl derivatives of the 5-HT2 agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane. J Med Chem. 1987;30:930-932.
50. Glennon RA, Raghupathi R, Bartyzel P, et al. Binding of phenylalkylamine derivatives at 5-HT1C and 5-HT2 serotonin receptors: evidence for a lack of selectivity. J Med Chem. 1992;35:734-740.
51. Monte AP, Marona-Lewicka D, Parker MA, et al. Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups. J Med Chem. 1996;39:2953-2961.
52. Body S, Cheung TH, Bezzina G, et al. Effects of d-amphetamine and DOI (2,5-dimethoxy-4-iodoamphetamine) on timing behavior: interaction between D1 and 5-HT2A receptors. Psychopharmacology (Berl). 2006;189:331-343.
53. Dimpfel W, Spuler M, Nichols DE. Hallucinogenic and stimulatory amphetamine derivatives: fingerprinting DOM, DOI, DOB, MDMA, and MBDB by spectral analysis of brain field potentials in the freely moving rat (Tele-Stereo-EEG). Psychopharmacology (Berl). 1989;98:297-303.
54. Ewald AH, Maurer HH. 2,5-Dimethoxyamphetamine-derived designer drugs: studies on the identification of cytochrome P450 (CYP) isoenzymes involved in formation of their main metabolites and on their capability to inhibit CYP2D6. Toxicol Lett. 2008;183:52-57.
55. Ho BT, Estevez V, Fritchie GE. The fate of 2,5-dimethoxy-4-methylamphetamine (STP, DOM) in monkey and rat brains. Brain Res. 1971;29:166-169.
56. Ho BT, Estevez V, Tansey LW, et al. Analogs of amphetamine. 5. Studies of excretory metabolites of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats. J Med Chem. 1971;14:158-160.
57. Johnson MP, Mathis CA, Shulgin AT, et al. [125I]-2-(2,5-dimethoxy-4-iodophenyl)aminoethane ([125I]-2C-I) as a label for the 5-HT2 receptor in rat frontal cortex. Pharmacol Biochem Behav. 1990;35:211-217.
58. Glennon RA, Titeler M, Lyon RA. A preliminary investigation of the psychoactive agent 4-bromo-2,5-dimethoxyphenethylamine: a potential drug of abuse. Pharmacol Biochem Behav. 1988;30:597-601.
59. Villalobos CA, Bull P, Saez P, et al. 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines are potent 5-HT2A receptor antagonists in Xenopus laevis oocytes. Br J Pharmacol. 2004;141:1167-1174.
60. Fantegrossi WE, Harrington AW, Eckler JR, et al. Hallucinogen-like actions of 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7) in mice and rats. Psychopharmacology (Berl ). 2005;181:496-503.
61. Lobos M, Borges Y, Gonzalez E, et al. The action of the psychoactive drug 2C-B on isolated rat thoracic aorta. Gen Pharmacol. 1992;23:1139-1142.
62. Saez P, Borges Y, Gonzalez E, et al. Alpha-adrenergic and 5-HT2-serotonergic effects of some beta-phenylethylamines on isolated rat thoracic aorta. Gen Pharmacol. 1994;25:211-216.
63. Braun U, Shulgin AT, Braun G, et al. Synthesis and body distribution of several iodine-131 labeled centrally acting drugs. J Med Chem. 1977;20:1543-1546.
64. Glennon RA, Kier LB, Shulgin AT. Molecular connectivity analysis of hallucinogenic mescaline analogs. J Pharm Sci. 1979;68:906-907.
65. Gupta SP, Bindal MC, Singh P. Quantitative structure-activity studies on hallucinogenic mescaline analogs using modified first order valence connectivity. Arzneim-Forsch. 1982;32:1223-1225.
66. Kier LB, Glennon RA. Progress with several models for the study of the SAR of hallucinogenic agents. NIDA Res Monogr. 1978;22:159-185.
67. Beuerle G, Kovar KA, Schulze-Alexandru M. Three-dimensional quantitative structure-activity relationships of hallucinogenic phenylalkanamine and tryptamine derivatives. Studies using comparative molecular field analysis (CoMFA). Quant Struct-Act Relat. 1997;16:447-458.
68. Bienfait B. Applications of high-resolution self-organizing maps to retrosynthetic and QSAR analysis. J Chem Inf Comput Sci. 1994;34:890-898.
69. Clare BW. The frontier orbital phase angles: novel QSAR descriptors for benzene derivatives, applied to phenylalkylamine hallucinogens. J Med Chem. 1998;41:3845-3856.
70. Klopman G, Macina OT. Use of the Computer Automated Structure Evaluation program in determining quantitative structure-activity relationships within hallucinogenic phenylalkylamines. J Theor Biol. 1985;113:637-648.
71. Mracec M, Mracec M, Kurunczi L, et al. QSAR study with steric (MTD), electronic and hydrophobicity parameters on psychotomimetic phenylalkylamines. THEOCHEM. 1996;367:139-149.
72. de Boer D, dos Reys LA, Pylon N, et al. Preliminary results on the urinary excretion of 2C-B (4-bromo-2,5-dimethoxyphenethylamine) and its metabolites in humans. Br J Pharmacol. 1999;127:41P.
73. Kanamori T, Inoue H, Iwata Y, et al. In vivo metabolism of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in the rat: identification of urinary metabolites. J Anal Toxicol. 2002;26:61-66.
74. Lin LC, Liu JT, Chou SH, et al. Identification of 2,5-dimethoxy-4-ethylthiophenethylamine and its metabolites in the urine of rats by gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2003;798:241-247.
75. Kanamori T, Tsujikawa K, Ohmae Y, et al. Excretory profile of 4-bromo-2,5-dimethoxy-phenethylamine (2C-B) in rat. J Health Sci. 2003;49:166-169.
76. Carmo H, Hengstler JG, de Boer D, et al. Comparative metabolism of the designer drug 4-methylthioamphetamine by hepatocytes from man, monkey, dog, rabbit, rat and mouse. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:198-205.
77. Kanamori T, Tsujikawa K, Ohmae Y, et al. A study of the metabolism of methamphetamine and 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in isolated rat hepatocytes. Forensic Sci Int. 2005;148:131-137.
78. Carmo H, Boer D, Remiao F, et al. Metabolism of the designer drug 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in mice, after acute administration. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;811:143-152.
79. Carmo H, Hengstler JG, de Boer D, et al. Metabolic pathways of 4-bromo-2,5-dimethoxyphenethylamine (2C-B): analysis of phase I metabolism with hepatocytes of six species including human. Toxicology. 2005;206:75-89.
80. Theobald DS, Maurer HH. Identification of monoamine oxidase and cytochrome P450 isoenzymes involved in the deamination of phenethylamine-derived designer drugs (2C-series). Biochem Pharmacol. 2007;73:287-297.
81. Meyer MR, Wilhelm J, Peters FT, et al. Beta-keto designer drugs: Studies on the metabolism of mephedrone and toxicological detection of mephedrone, butylone and methylone in urine using gas chromatography-mass spectrometry. Anal Bioanal Chem. 2010;397:1225-1233.
82. Roesner P, Junge T, Fritschi G, et al. Neue synthetische Drogen: Piperazin-, Procyclidin- und alpha-Aminopropiophenonderivate. Toxichem Krimtech. 1999;66:81-90.
83. Maddox VH, Godefroi EF, Parcell RF. Synthesis of phencyclidine and other 1-arylcyclohexylamines. J Med Chem. 1965;8:230-235.
84. Rang HP, Dale MM, Ritter JM, eds. Pharmacology, 4th ed. London: Churchill Livingston; 1999.
85. Takeda H, Gazzara RA, Howard SG. Phenylcyclohexylamine: effect of a metabolite of phencyclidine on the efflux of dopamine in the rat. Neuropharmacology. 1986;25:1341-1345.
86. Sauer C, Peters FT, Schwaninger AE, et al. Identification of cytochrome P450 enzymes involved in the metabolism of the designer drugs N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA) and N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA). Chem Res Toxicol. 2008;21:1949-1955.
87. Sauer C, Peters FT, Schwaninger AE, et al. Investigations on the cytochrome P450 (CYP) isoenzymes involved in the metabolism of the designer drugs N-(1-phenylcyclohexyl)-2-ethoxyethanamine and N-(1-phenylcyclohexyl)-2-methoxyethanamine. Biochem Pharmacol. 2009;77:444-450.
88. Shellard EJ. The alkaloids of Mitragyna with special reference to those of Mitragyna speciosa, Korth. Bull Narc. 1974;26:41-55.
89. Ponglux D, Wongseripipatana S, Takayama H, et al. A new indole alkaloid, 7 alpha-hydroxy-7H-mitragynine, from Mitragyna speciosa in Thailand. Planta Med. 1994;60:580-581.
90. Matsumoto K, Horie S, Ishikawa H, et al. Antinociceptive effect of 7-hydroxymitragynine in mice: discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa. Life Sci. 2004;74:2143-2155.
91. Suwanlert S. A study of kratom eaters in Thailand. Bull Narc. 1975;27:21-27.
92. Jansen KL, Prast CJ. Ethnopharmacology of kratom and the Mitragyna alkaloids. J Ethnopharmacol. 1988;23:115-119.
93. Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm Bull (Tokyo). 2004;52:916-928.
94. Babu KM, McCurdy CR, Boyer EW. Opioid receptors and legal highs: Salvia divinorum and Kratom. Clin Toxicol (Phila). 2008;46:146-152.
Keywords:

drugs of abuse; designer drugs; herbal drugs; pharmacology; metabolism

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