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5,6-Methylenedioxy-2-aminoindane (MDAI) is a drug developed in the 1990s by a team led by David E. Nichols at Purdue University. It acts as a non-neurotoxic and highly selective serotonin releasing agent (SSRA) in vitro and produces entactogen effects in humans.
The chemical structure of MDAI is indirectly derived from that of the illicit drug MDA, but the alpha-methyl group of the alkylamino amphetamine side chain has been bound back to the benzene nucleus to form an indane ring system, which changes its pharmacological properties substantially.
MDAI can be produced from 3-(3,4-Methylenedioxyphenyl)propionic acid which is converted to the acid chloride and then heated to produce 5,6-Methylenedioxy-1-indanone. Treatment of the indanone with amyl nitrite in methanol with HC1 afforded the hydroxyimino ketone. This is reduced to the 2-aminoindan following a modification of Nichols' earlier method from a paper discussing DOM analogues, using a Pd/C catalyst in glacial acetic acid with catalytic H2SO4.
MDAI has been shown to inhibit the reuptake of serotonin, dopamine, and norepinephrine with IC50 values of 512nM, 5,920nM, and 1,426nM, respectively. This demonstrates that MDAI has selective affinity for the serotonin transporter (SERT). In animals treated with reserpine and MDAI, greater extracellular concentrations of monoamine neural transmitters resulted, most significantly serotonin. This result indicates that MDAI is a potent releaser of serotonin, while effectively inhibiting the reuptake of serotonin. For comparison, MDAI is similar in potency with releasing serotonin to MDA but significantly less potent than MDMA.
The family of drugs typified by MDMA produce their effects through multiple mechanisms of action in the body, and consequently produce three distinct cues which animals can be trained to respond to: a stimulant cue typified by drugs such as methamphetamine, a hallucinogen cue typified by drugs such as LSD and DOM, and an "entactogen-like" cue which is produced by drugs such as MDAI and MBDB. These drugs cause drug-appropriate responses in animals trained to recognize the effects of MDMA, but do not produce responses in animals trained selectively to respond to stimulants or hallucinogens. Because these compounds selectively release serotonin in the brain but have little effect on dopamine or noradrenaline levels, they can produce empathogenic effects but without any stimulant action, instead being somewhat sedating.
Use in scientific research
MDAI and other similar drugs have been widely used in scientific research, as they are able to replicate many of the effects of MDMA, but without causing the neurotoxicity which may be associated with MDMA and some related drugs. No tests have been performed on cardiovascular toxicity.
Use as a recreational drug
MDAI has been advertised as a designer drug. It started to be sold online from around 2007, but reached peak popularity between about 2010-2012, after bans on mephedrone came into effect in various countries. Internet-sourced products claimed to be MDAI have been shown variously to contain mephedrone or other substituted cathinone derivatives, and mixed compositions of inorganic substances, while generally containing no MDAI. Numbers of Internet searches have been considerably higher in the UK compared with Germany and the USA. MDAI is only non-neurotoxic in isolation but may become neurotoxic when mixed with other drugs. Three deaths were linked to MDAI use in the UK during 2011-2012, all involving symptoms consistent with serotonin syndrome. Two of these also involved other drugs while one death appeared to be from MDAI alone.
- Nichols, D. E.; Brewster, W. K.; Johnson, M. P.; Oberlender, R.; Riggs, R. M. (1990). "Nonneurotoxic tetralin and indan analogs of 3,4-(methylenedioxy)amphetamine (MDA)". Journal of Medicinal Chemistry 33 (2): 703–10. PMID 1967651. doi:10.1021/jm00164a037.
- Nichols, D. E.; Barfknecht, C. F.; Long, J. P.; Standridge, R. T.; Howell, H. G.; Partyka, R. A.; Dyer, D. C. (1974). "Potential psychotomimetics. 2. Rigid analogs of 2,5-dimethoxy-4-methylphenylisopropylamine (DOM, STP)". Journal of Medicinal Chemistry 17 (2): 161. doi:10.1021/jm00248a004.
- Johnson MP, Conarty PF, Nichols DE. [3H]monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues. Eur J Pharmacol. 1991 Jul 23;200(1):9-16. PMID 1685125
- Steele TD, Nichols DE, Yim GK. Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monoamines into synaptosomes from different regions of rat brain. Biochemical Pharmacology. 1987 Jul 15;36(14):2297-303. PMID 2886126
- Oberlender R, Nichols DE. Drug discrimination studies with MDMA and amphetamine. Psychopharmacology (Berlin). 1988;95(1):71-6. PMID 2898791
- Nichols DE. Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens. Journal of Psychoactive Drugs. 1986 Oct-Dec;18(4):305-13. PMID 2880944
- Oberlender R, Nichols DE. (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative stimulus in studies of 3,4-methylenedioxy-methamphetamine-like behavioral activity. Journal of Pharmacology and Experimental Therapeutics. 1990 Dec;255(3):1098-106. PMID 1979813
- Oberlender R, Nichols DE. Structural variation and (+)-amphetamine-like discriminative stimulus properties. Pharmacology, Biochemistry and Behaviour. 1991 Mar;38(3):581-6. doi:10.1016/0091-3057(91)90017-V PMID 2068194
- Marona-Lewicka D, Nichols DE. Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan. European Journal of Pharmacology. 1994 Jun 2;258(1-2):1-13. doi:10.1016/0014-2999(94)90051-5 PMID 7925587
- Kovar KA. Chemistry and pharmacology of hallucinogens, entactogens and stimulants. Pharmacopsychiatry. 1998 Jul;31 Suppl 2:69-72. PMID 9754836
- Nichols DE, Johnson MP, Oberlender R. 5-Iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine. Pharmacology, Biochemistry and Behaviour. 1991 Jan;38(1):135-9. PMID 1826785
- Johnson MP, Frescas SP, Oberlender R, Nichols DE. Synthesis and Pharmacological Examination of 1-(3-Methoxy-4-methylphenyl)-2-aminopropane and 5-Methoxy-6-methyl-2-aminoindan: Similarities to 3,4-(Methylenedioxy)methamphetamine (MDMA). Journal of Medicinal Chemistry 1991;34:1662-1668.
- Johnson MP, Huang XM, Nichols DE. Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue. Pharmacology, Biochemistry and Behaviour. 1991 Dec;40(4):915-22. PMID 1726189
- Nichols DE, Marona-Lewicka D, Huang X, Johnson MP. Novel serotonergic agents. Drug Design and Discovery. 1993;9(3-4):299-312. PMID 8400010
- Sprague JE, Johnson MP, Schmidt CJ, Nichols DE. Studies on the mechanism of p-chloroamphetamine neurotoxicity. Biochemical Pharmacology. 1996 Oct 25;52(8):1271-7. PMID 8937435
- Cozzi NV, Frescas S, Marona-Lewicka D, Huang X, Nichols DE. Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential. Pharmacology, Biochemistry and Behaviour. 1998 Mar;59(3):709-15. doi:10.1016/S0091-3057(97)00557-1 PMID 9512076
- Gallagher, C. T.; Assi, S.; Stair, J. L.; Fergus, S.; Corazza, O.; Corkery, J. M.; Schifano, F. (2012). "5,6-Methylenedioxy-2-aminoindane: From laboratory curiosity to 'legal high'". Human Psychopharmacology: Clinical and Experimental 27 (2): 106–112. PMID 22389075. doi:10.1002/hup.1255.
- Brandt, S. D.; Sumnall, H. R.; Measham, F.; Cole, J. (2010). "Second generation mephedrone. The confusing case of NRG-1". BMJ 341: c3564. PMID 20605894. doi:10.1136/bmj.c3564.
- Corkery, J. M.; Elliott, S.; Schifano, F.; Corazza, O.; Ghodse, A. H. (2013). "MDAI (5,6-methylenedioxy-2-aminoindane; 6,7-dihydro-5H-cyclopenta\f]\1,3]benzodioxol-6-amine; 'sparkle'; 'mindy') toxicity: A brief overview and update". Human Psychopharmacology: Clinical and Experimental 28 (4): 345. doi:10.1002/hup.2298.