MDAI

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MDAI
MDAI.svg
MDAI 3D ball.png
Clinical data
Routes of
administration		 Oral
ATC code
  • none
Legal status
Legal status
  • Illegal in China
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C10H11NO2
Molar mass 177.1998 g/mol
3D model (Jmol)

MDAI (5,6-methylenedioxy-2-aminoindane) 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.

Chemistry[edit]

The chemical structure of MDAI is indirectly derived from that of the illicit drug MDA, but the alpha-methyl group of the alkyl amino 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[1] 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 HCl afforded the hydroxyimino ketone. This is reduced to the 2-aminoindan following a modification of Nichols' earlier method from a paper discussing DOM analogues,[2] using a Pd/C catalyst in glacial acetic acid with catalytic H2SO4.

Pharmacology[edit]

MDAI has been shown to inhibit the reuptake of serotonin, dopamine, and norepinephrine with IC50 values of 512 nM, 5,920 nM, and 1,426 nM, 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.[3]

Effects[edit]

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.[4][5][6][7][8][9][10]

Very high doses can be fatal in rats with a 50% fatality rate for those subcutaneously injected with 28 mg/kg of MDAI. This is a result of the way serotonin release interferes with thermoregulation.[11]

Use in scientific research[edit]

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.[1][12][13][14][15][16][17]

Use as a recreational drug[edit]

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. The number of internet searches for MDAI has been considerably higher in the UK compared to Germany and the USA.[18] MDAI is only non-neurotoxic in isolation but may become neurotoxic when mixed with other drugs.[19] 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.[20]

Legal Status[edit]

China[edit]

As of October 2015 MDAI is a controlled substance in China.[21]

MDAI is illegal in Denmark as of September 2015.[22]

As of December 2011 MDAI is a controlled substance in Switzerland [23]

See also[edit]

References[edit]

  1. ^ a b 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. doi:10.1021/jm00164a037. PMID 1967651. 
  2. ^ 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): 161–6. doi:10.1021/jm00248a004. PMID 4809251. 
  3. ^ Johnson, M. P.; Conarty, P. F.; Nichols, D. E. (1991). "3Hmonoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues". European Journal of Pharmacology. 200 (1): 9–16. doi:10.1016/0014-2999(91)90659-e. PMID 1685125. 
  4. ^ Steele, T. D.; Nichols, D. E.; Yim, G. K. (1987). "Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of 3Hmonoamines into synaptosomes from different regions of rat brain". Biochemical Pharmacology. 36 (14): 2297–303. doi:10.1016/0006-2952(87)90594-6. PMID 2886126. 
  5. ^ Oberlender, R; Nichols, D. E. (1988). "Drug discrimination studies with MDMA and amphetamine". Psychopharmacology. 95 (1): 71–6. doi:10.1007/bf00212770. PMID 2898791. 
  6. ^ Nichols, D. E. (1986). "Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: Entactogens". Journal of Psychoactive Drugs. 18 (4): 305–13. doi:10.1080/02791072.1986.10472362. PMID 2880944. 
  7. ^ Oberlender, R; Nichols, D. E. (1990). "(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative stimulus in studies of 3,4-methylenedioxy-methamphetamine-like behavioral activity". The Journal of Pharmacology and Experimental Therapeutics. 255 (3): 1098–106. PMID 1979813. 
  8. ^ Oberlender, R; Nichols, D. E. (1991). "Structural variation and (+)-amphetamine-like discriminative stimulus properties". Pharmacology, Biochemistry, and Behavior. 38 (3): 581–6. doi:10.1016/0091-3057(91)90017-V. PMID 2068194.  PMID
  9. ^ Marona-Lewicka, D; Nichols, D. E. (1994). "Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan". European Journal of Pharmacology. 258 (1–2): 1–13. doi:10.1016/0014-2999(94)90051-5. PMID 7925587. 
  10. ^ Kovar, K. A. (1998). "Chemistry and pharmacology of hallucinogens, entactogens and stimulants". Pharmacopsychiatry. 31 Suppl 2: 69–72. doi:10.1055/s-2007-979349. PMID 9754836. 
  11. ^ Tomáš Páleníčeka, Eva Lhotkováa, Monika Žídkováb, Marie Balíkováb, Martin Kuchařa, d, Michal Himld, Petra Mikšátkováa, Martin Čegane, Karel Valeša, Filip Tylša, Rachel R. Horsleya (2016-08-01). "Emerging toxicity of 5,6-methylenedioxy-2-aminoindane (MDAI): Pharmacokinetics, behaviour, thermoregulation and LD50 in rats". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 69: 49–59. doi:10.1016/j.pnpbp.2016.04.004. 
  12. ^ Nichols, DE; Johnson, MP; Oberlender, R (January 1991). "5-Iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine". Pharmacol. Biochem. Behav. 38: 135–9. doi:10.1016/0091-3057(91)90601-w. PMID 1826785. 
  13. ^ Johnson, MP; Frescas, SP; Oberlender, R; Nichols, DE (1991). "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. 34: 1662–1668. doi:10.1021/jm00109a020. PMID 1674539. 
  14. ^ Johnson, MP; Huang, XM; Nichols, DE (Dec 1991). "Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue". Pharmacology, Biochemistry and Behaviour. 40 (4): 915–22. doi:10.1016/0091-3057(91)90106-c. PMID 1726189. 
  15. ^ Nichols, DE; Marona-Lewicka, D; Huang, X; Johnson, MP (1993). "Novel serotonergic agents". Drug Des Discov. 9: 299–312. PMID 8400010. 
  16. ^ Sprague, JE; Johnson, MP; Schmidt, CJ; Nichols, DE (Oct 1996). "Studies on the mechanism of p-chloroamphetamine neurotoxicity". Biochemical Pharmacology. 52 (8): 1271–7. doi:10.1016/0006-2952(96)00482-0. PMID 8937435. 
  17. ^ 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
  18. ^ 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. doi:10.1002/hup.1255. PMID 22389075. 
  19. ^ Brandt, S. D.; Sumnall, H. R.; Measham, F.; Cole, J. (2010). "Second generation mephedrone. The confusing case of NRG-1". BMJ. 341: c3564. doi:10.1136/bmj.c3564. PMID 20605894. 
  20. ^ 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): 345–355. doi:10.1002/hup.2298. 
  21. ^ "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in Chinese). China Food and Drug Administration. 27 September 2015. Retrieved 1 October 2015. 
  22. ^ "Lists of euphoriant substances subject to control in Denmark". The Danish Medicines Agency. September 2015. 
  23. ^ https://www.admin.ch/opc/de/classified-compilation/20101220/201112010000/812.121.11.pdf
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