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http://dx.doi.org/10.4062/biomolther.2017.141

Evaluation of the Abuse Potential of Novel Amphetamine Derivatives with Modifications on the Amine (NBNA) and Phenyl (EDA, PMEA, 2-APN) Sites  

Custodio, Raly James Perez (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
Botanas, Chrislean Jun (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
Yoon, Seong Shoon (Center for Safety Pharmacology, Korea Institute of Toxicology)
de la Pena, June Bryan (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
dela Pena, Irene Joy (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
Kim, Mikyung (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
Woo, Taeseon (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
Seo, Joung-Wook (Center for Safety Pharmacology, Korea Institute of Toxicology)
Jang, Choon-Gon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
Kwon, Yong Ho (Department of Life and Nanopharmaceutical Sciences, Kyung Hee University)
Kim, Nam Yong (Department of Life and Nanopharmaceutical Sciences, Kyung Hee University)
Lee, Yong Sup (Department of Life and Nanopharmaceutical Sciences, Kyung Hee University)
Kim, Hee Jin (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
Cheong, Jae Hoon (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
Publication Information
Biomolecules & Therapeutics / v.25, no.6, 2017 , pp. 578-585 More about this Journal
Abstract
Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.
Keywords
Amphetamine derivatives; New Psychoactive Substances; Conditioned-place Preference; Self-administration; D1 & D2 Dopamine receptors; Abuse potential;
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1 Marona-Lewicka, D., Rhee, G. S., Sprague, J. E. and Nichols, D. E. (1996) Reinforcing effects of certain serotonin-releasing amphetamine derivatives. Pharmacol. Biochem. Behav. 53, 99-105.   DOI
2 Matsumoto, T., Maeno, Y., Kato, H., Seko-Nakamura, Y., Monma-Ohtaki, J., Ishiba, A., Nagao, M. and Aoki, Y. (2014) 5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis. Eur. Neuropsychopharmacol. 24, 1362-1370.   DOI
3 McPherson, C. S. and Lawrence, A. J. (2007) The nuclear transcription factor CREB: involvement in addiction, deletion models and looking forward. Curr. Neuropharmacol. 5, 202-212.   DOI
4 Moore, K. A., Lichtman, A. H., Poklis, A. and Borzelleca, J. F. (1995) ${\alpha}$-Benzyl-N-methylphenethylamine (BNMPA), an impurity of illicit methamphetamine synthesis: pharmacological evaluation and interaction with methamphetamine. Drug Alcohol Depend. 39, 83-89.   DOI
5 Robaa, D., Enzensperger, C., Abulazm, S. E., Hefnawy, M. M., El-Subbagh, H. I., Wani, T. A. and Lehmann, J. (2011) Chiral indolo[3,2-f][3]benzazecine-type dopamine receptor antagonists: synthesis and activity of racemic and enantiopure derivatives. J. Med. Chem. 54, 7422-7426.   DOI
6 Salomon, L., Lanteri, C., Glowinski, J. and Tassin, J. P. (2006) Behavioral sensitization to amphetamine results from an uncoupling between noradrenergic and serotonergic neurons. Proc. Natl. Acad. Sci. U.S.A. 103, 7476-7481.   DOI
7 Taniguchi, M., Yamamoto, Y. and Nishi, K. (2010) A technique combining trifluoroacetyl derivatization and gas chromatography-mass spectrometry to distinguish methamphetamine and its 4-substituted analogs. J. Mass Spectrom. 45, 1473-1476.   DOI
8 Tettey, J., Wong, Y. L., Levissianos, S., Eichinger, N., Soe, T. N., Kelley, S. and Umapornsakula, A. (2013) Patterns and Trends of Amphetamine-Type Stimulants and Other Drugs: Challenges for Asia and the Pacific. A Report from the Global SMART Programme. pp. 1-162.
9 Thanos, P. K., Volkow, N. D., Freimuth, P., Umegaki, H., Ikari, H., Roth, G., Ingam, D. K. and Hitzemann, R. (2001) Overexpression of dopamine D2 receptors reduces alcohol self-administration. J. Neurochem. 78, 1094-1103.   DOI
10 United Nations Office on Drugs and Crime (2011) Amphetamines and ecstasy. 2011 Global ATS Assessment. United Nations Publication. Available from: https://www.unodc.org/documents/ATS/ATS_Global_Assessment_2011.pdf/.
11 United Nations Office on Drugs and Crime (2016) World Drug Report 2016. United Nations publication. Available from: https://www.unodc.org/doc/wdr2016/WORLD_DRUG_REPORT_2016_web.pdf/.
12 Vallejos, G., Fierro, A., Renzende, M. C., Sepúlveda-Boza, S. and Reyes-Parada, M. (2005) Heteroarylisopropylamines as MAO inhibitors. Bioorg. Med. Chem. 13, 4450-4457.   DOI
13 Flomenbaum, N. E., Goldfrank, L. R., Hoffman, R. S., Howland, M. A., Lewin, N. A. and Nelson, L. S. (2006) Goldfrank's Toxicologic Emergencies, 8th edition. McGraw Hill.
14 de la Pena, J. B., Yoon, S. Y., de la Pena, I. C., Lee, H. L., de la Pena, I. J. and Cheong, J. H. (2013) Pre-exposure to related substances induced place preference and self-administration of the NMDA receptor antagonist-benzodiazepine combination, zoletil. Behav. Pharmacol. 24, 20-28.   DOI
15 Drug Enforcement Administration (2011) Drugs of Abuse: 2011 Edition. A DEA Resource Guide. US Department of Justice.
16 Funada, M., Aoo, N. and Wada, K. (2014) Rewarding effects of N-methyl-1-(4-Methoxyphenyl)-2-aminopropane (PMMA) in mice: role of modifications of dopamine system mediated through its monoamine oxidase inhibition. J. Addict. Res. Ther. 5, 172.
17 Halberstadt, A. L., Powell, S. B. and Geyer, M. A. (2013) Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice. Neuropharmacology 70, 218-227.   DOI
18 Kalant, H. (2001) The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. CMAJ 165, 917-928.
19 Kang, S., Paul, K., Hankosky, E. R., Cox, C. L. and Gulley, J. M. (2016) D1 receptor-mediated inhibition of medial prefrontal cortex neurons is disrupted in adult rats exposed to amphetamine in adolescence. Neuroscience 324, 40-49.   DOI
20 Kim, J. Y., Shin, H. S. and In, M. K. (2010) Determination of amphetamine-type stimulants, ketamine and metabolites in fingernails by gas chromatography-mass spectrometry. Forensic Sci. Int. 194, 108-114.   DOI
21 Lüscher, C. and Malenka, R. C. (2011) Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69, 650-663.   DOI
22 Cain, M. E., Denehy, E. R. and Bardo, M. T. (2008) Individual differences in amphetamine self-administration: The role of the central nucleus of the amygdala. Neuropsychopharmacology 33, 1149-1161.   DOI
23 Ali, R. (2006) WHO multi-site project on methamphetamine induced psychosis: a descriptive report on findings from participating countries. Drug & Alcohol Services South Australia.
24 Berman, S., O'Neill, J., Fears, S., Bartzokis, G. and London, E. D. (2008) Abuse of amphetamines and structural abnormalities in the brain. Ann. N. Y. Acad. Sci. 1141, 195-220.   DOI
25 Berman, S. M., Kuczenski, R., McCracken, J. T. and London, E. D. (2009) Potential adverse effects of amphetamine treatment on brain and behavior: a review. Mol. Psychiatry 14, 123-142.   DOI
26 Dean, B. V., Stellpflug, S. J., Burnett, A. M., and Engebretsen, K. M. (2013) 2C or not 2C: phenethylamine designer drug review. J. Med. Toxicol. 9, 172-178.   DOI
27 Sitte, H. H. and Freissmuth, M. (2015) Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol. Sci. 36, 41-50.   DOI
28 Schatzberg, A. F. and Nemeroff, C. B. (2009) The American Psychiatric Publishing Textbook Of Psychopharmacology. American Psychiatric Pub.