Substituted 2-aminoindane

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Chemical structure of 2-aminoindane (2-AI), the parent compound of the substituted 2-aminoindanes. 2-Aminoindane.svg
Chemical structure of 2-aminoindane (2-AI), the parent compound of the substituted 2-aminoindanes.
Chemical structure of MDAI, one of the most well-known 2-aminoindanes. MDAI.svg
Chemical structure of MDAI, one of the most well-known 2-aminoindanes.

A substituted 2-aminoindane is a derivative of 2-aminoindane (2-AI) with one or more chemical substituents. [1] [2] [3] [4] They are cyclized phenethylamines and are structurally related to amphetamines like amphetamine and MDMA. [1] [3]

Contents

Many 2-aminoindanes are known to act as monoamine releasing agents and/or receptor modulators. [1] [3] [4] They include psychoactive drugs, more specifically entactogens, stimulants, and psychedelics, and have been encountered as novel designer drugs. [1] [3] [5] [6] [4] However, 2-aminoindanes are more selective for serotonin and/or norepinephrine release and are less effective at inducing dopamine release than their phenethylamine counterparts, are consequently less euphoric, and have not gained widespread popularity as recreational drugs. [5] There is interest in entactogenic 2-aminoindanes for potential medical use, such as treatment of psychiatric disorders. [5] [7] [8] One 2-aminoindane, MEAI, has been suggested as a possible alcohol alternative and substitute with better safety and less addictive potential. [9]

Examples of 2-aminoindanes acting as monoamine releasing agents include 2-AI itself, NM-2-AI, MDAI, [10] [11] MMAI, MEAI (5-MeO-2-AI), and 5-IAI, [12] among others. [1] [3] [4] DOM-AI is the 2-aminoindane analogue of the DOx psychedelic DOM and shows psychedelic-like effects in animals similarly but less potently. [2] [13] [14] [15] [16] 2-Aminoindanes acting via other actions include aprindine, indantadol, and PNU-99,194, among others.

Use and effects

2-Aminoindanes acting as monoamine releasing agents variably produce entactogenic and/or stimulant effects. [5] Serotonin-releasing 2-aminoindanes are described as less stimulating and much less euphoric than their phenethylamine counterparts. [5] The next-day emotional hangover present with MDMA seems to be absent with these 2-aminoindanes, at least based on anecdotal user reports. [5]

Pharmacology

Pharmacodynamics

Activities of 2-aminoindanes and their amphetamine relatives
Compound Monoamine release (EC50 Tooltip half-maximal effective concentration, nM)Ref
5-HT Tooltip Serotonin releasing agent NE Tooltip Norepinephrine releasing agent DA Tooltip Dopamine releasing agent
2-AI >10,00086439 [4]
MDAI 1141171,334 [4]
MDMAI NDNDNDND
MEAI 1348612,646 [4]
MMAI 313,101>10,000 [4]
d-Amphetamine 698–1,7656.6–7.25.8–24.8 [20] [21] [22] [23] [24]
MDA 160–16247–108106–190 [25] [22] [26]
MDMA 50–8554–11051–278 [20] [27] [28] [25] [26]
3-MA ND58.0103 [22]
MMA NDNDNDND
Notes: The smaller the value, the more strongly the compound produces the effect. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: [4]

2-Aminoindanes are known to act as monoamine releasing agents, including of serotonin, norepinephrine, and/or dopamine, among other actions such as α2-adrenergic receptor interactions. [5] [4] However, they are more selective for induction of serotonin and/or norepinephrine release than induction of dopamine release. [5] [4] This is thought to result in serotonin-releasing 2-aminoindanes having retained entactogenic effects but greatly reduced stimulating and euphoriant effects compared to their amphetamine counterparts. [5] [4]

Serotonin-releasing 2-aminoindanes show much less or no serotonergic neurotoxicity relative to MDMA. [5] [2] However, combination of serotonin-releasing 2-aminoindanes like MDAI or MMAI with amphetamine results in serotonergic neurotoxicity similar to that with MDMA. [5] [29] [30] [31] It is thought that robust simultaneous release of both serotonin and dopamine may be required for serotonergic neurotoxicity with MDMA-like drugs and that this is able to occur when serotonin-releasing aminoindanes are combined with an efficacious dopamine releaser like amphetamine. [5] [29] [30] [31]

History

The serotonin-releasing 2-aminoindanes like MDAI were developed by David E. Nichols and colleagues at Purdue University and were first described in 1990 followed by further publications throughout the rest of the 1990s. [10] [32] [33] [34] [35] [36] [37]

List of substituted 2-aminoindanes

Monoamine releasing agents

Other agents

Indanorex is a 2-aminomethylindane, wherein the amino side chain has a methyl spacer. It was previously marketed under the brand name Dietor as a stimulant and appetite suppressant.

2-Aminotetralin (2-AT) and derivatives such as 6,7-methylenedioxy-2-aminotetralin (MDAT) and MDMAT are analogues of the 2-aminoindanes.

Jimscaline, 2CB-Ind, and AMMI are derivatives of 1-aminomethylindane, an indane- and amine-containing compound related to 1-aminoindane.

A number of notable derivatives of 1-aminoindane, a positional isomer of 2-AI, exist, such as rasagiline and ladostigil, among others.

See also

References

  1. 1 2 3 4 5 Sainsbury PD, Kicman AT, Archer RP, King LA, Braithwaite RA (2011). "Aminoindanes--the next wave of 'legal highs'?". Drug Test Anal. 3 (7–8): 479–482. doi:10.1002/dta.318. PMID   21748859.
  2. 1 2 3 Brandt, Simon D.; Braithwaite, Robin A.; Evans-Brown, Michael; Kicman, Andrew T. (2013). "Aminoindane Analogues". Novel Psychoactive Substances. Elsevier. pp. 261–283. doi:10.1016/b978-0-12-415816-0.00011-0. ISBN   978-0-12-415816-0 . Retrieved 2 November 2025.
  3. 1 2 3 4 5 6 Pinterova N, Horsley RR, Palenicek T (2017). "Synthetic Aminoindanes: A Summary of Existing Knowledge". Front Psychiatry. 8 236. doi: 10.3389/fpsyt.2017.00236 . PMC   5698283 . PMID   29204127.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 Halberstadt AL, Brandt SD, Walther D, Baumann MH (March 2019). "2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors". Psychopharmacology (Berl). 236 (3): 989–999. doi:10.1007/s00213-019-05207-1. PMC   6848746 . PMID   30904940.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Oeri HE (May 2021). "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". J Psychopharmacol. 35 (5): 512–536. doi:10.1177/0269881120920420. PMC   8155739 . PMID   32909493.
  6. 1 2 Luethi D, Liechti ME (April 2020). "Designer drugs: mechanism of action and adverse effects". Arch Toxicol. 94 (4): 1085–1133. Bibcode:2020ArTox..94.1085L. doi:10.1007/s00204-020-02693-7. PMC   7225206 . PMID   32249347.
  7. ↑ Pitts EG, Curry DW, Hampshire KN, Young MB, Howell LL (February 2018). "(±)-MDMA and its enantiomers: potential therapeutic advantages of R(-)-MDMA". Psychopharmacology (Berl). 235 (2): 377–392. doi:10.1007/s00213-017-4812-5. PMID   29248945.
  8. ↑ Shimshoni JA, Sobol E, Golan E, Ben Ari Y, Gal O (March 2018). "Pharmacokinetic and pharmacodynamic evaluation of 5-methoxy-2-aminoindane (MEAI): A new binge-mitigating agent". Toxicol Appl Pharmacol. 343: 29–39. Bibcode:2018ToxAP.343...29S. doi:10.1016/j.taap.2018.02.009. PMID   29458138.
  9. ↑ Slezak, Michael (2015). "A not-so-bitter pill". New Scientist. 225 (3002): 8–9. Bibcode:2015NewSc.225....8S. doi:10.1016/S0262-4079(15)60011-2 . Retrieved 2 November 2025.
  10. 1 2 3 Gallagher CT, Assi S, Stair JL, Fergus S, Corazza O, Corkery JM, Schifano F (March 2012). "5,6-Methylenedioxy-2-aminoindane: from laboratory curiosity to 'legal high'". Hum Psychopharmacol. 27 (2): 106–112. doi:10.1002/hup.1255. PMID   22389075.
  11. 1 2 3 Corkery JM, Elliott S, Schifano F, Corazza O, Ghodse AH (July 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". Hum Psychopharmacol. 28 (4): 345–355. doi:10.1002/hup.2298. PMID   23881883. Doses range from 70–300 mg; typical doses appear to be 150–200 mg of active ingredient (equivalent to half of a 300 mg capsule or a whole 200 mg capsule). A 'low' dose of 70–80 mg produces subtle but noticeable effects; a strong dose is considered to be 250–300 mg. Redosing often occurs; typically a 'booster' of 100–150 mg is administered after the initial positive effects have worn off (Drugs-Forum, 2009a; Bluelight, 2010a; Herbalhighs, 2012a; Partyvibe, 2012).
  12. 1 2 3 Coppola M, Mondola R (March 2013). "5-Iodo-2-aminoindan (5-IAI): chemistry, pharmacology, and toxicology of a research chemical producing MDMA-like effects". Toxicol Lett. 218 (1): 24–29. Bibcode:2013ToxL..218...24C. doi:10.1016/j.toxlet.2013.01.008. PMID   23347877.
  13. ↑ Nichols DE, Barfknecht CF, Long JP, Standridge RT, Howell HG, Partyka RA, Dyer DC (February 1974). "Potential psychotomimetics. 2. Rigid analogs of 2,5-dimethoxy-4-methylphenylisopropylamine (DOM, STP)". Journal of Medicinal Chemistry. 17 (2): 161–166. doi:10.1021/jm00248a004. PMID   4809251.
  14. ↑ Nichols DE, Weintraub HJ, Pfister WR, Yim GK (1978). "The use of rigid analogues to probe hallucinogen receptors" (PDF). NIDA Research Monograph (22): 70–83. PMID   101889. Archived from the original (PDF) on August 5, 2023.
  15. ↑ Nichols DE (August 1981). "Structure-activity relationships of phenethylamine hallucinogens". Journal of Pharmaceutical Sciences. 70 (8): 839–849. Bibcode:1981JPhmS..70..839N. doi:10.1002/jps.2600700802. PMID   7031221.
  16. ↑ Nichols DE, Brewster WK, Johnson MP, Oberlender R, Riggs RM (February 1990). "Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA)". Journal of Medicinal Chemistry. 33 (2): 703–710. doi:10.1021/jm00164a037. PMID   1967651. In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine [DOM] were also evaluated. [...] Compounds 5a and 5b did not substitute in MDMA-trained rats, although 5a substituted in LSD-trained rats, but with relatively low potency compared to its open-chain counterpart. [...] The results of the drug discrimination studies in rats are presented in Tables I and II. In the LSD-trained rats, stimulus generalization did not occur with any of the compounds 3a,b, 4a,b or 5b. [...] However, indan 5a gave full substitution, with an ED50 = 2.18 mg/kg, approximately 1/15 the potency of the hallucinogen DOM in this assay.24 Earlier studies of this compound, using disruption of a conditioned-avoidance response, did not produce results suggestive of hallucinogenlike activity.18
  17. ↑ Luethi D, Liechti ME (October 2018). "Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics". Int J Neuropsychopharmacol. 21 (10): 926–931. doi:10.1093/ijnp/pyy047. PMC   6165951 . PMID   29850881.
  18. ↑ Varì, M. Rosaria; Pichini, Simona; Giorgetti, Raffaele; Busardò, Francesco P. (2019). "New psychoactive substances—Synthetic stimulants". WIREs Forensic Science. 1 (2) e1197. doi: 10.1002/wfs2.1197 . ISSN   2573-9468. "Recommended" oral doses for a mild MDAI effect are 100–150 mg, 10–20 mg for 2-AI, and approximately 100 mg for 5-IAI.
  19. ↑ Zawilska JB (2015). ""Legal Highs"--An Emerging Epidemic of Novel Psychoactive Substances". Int Rev Neurobiol. International Review of Neurobiology. 120: 273–300. doi:10.1016/bs.irn.2015.02.009. ISBN   978-0-12-802978-7. PMID   26070762.
  20. 1 2 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707. S2CID   15573624.
  21. ↑ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC   3572453 . PMID   23072836.
  22. 1 2 3 Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN   978-0-470-11790-3. OCLC   181862653. OL   18589888W.
  23. ↑ Glennon RA, Dukat M (2017). "Structure-Activity Relationships of Synthetic Cathinones". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. Vol. 32. pp. 19–47. doi:10.1007/7854_2016_41. ISBN   978-3-319-52442-9. PMC   5818155 . PMID   27830576.
  24. ↑ Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID   11680410. Archived from the original (PDF) on August 5, 2023. RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). [...]
  25. 1 2 Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL (June 2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology. 63 (6): 1223–1229. doi:10.1124/mol.63.6.1223. PMID   12761331. S2CID   839426.
  26. 1 2 Brandt SD, Walters HM, Partilla JS, Blough BE, Kavanagh PV, Baumann MH (December 2020). "The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats". Psychopharmacology (Berl). 237 (12): 3703–3714. doi:10.1007/s00213-020-05648-z. PMC   7686291 . PMID   32875347.
  27. ↑ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC   3306880 . PMID   22169943.
  28. ↑ Marusich JA, Antonazzo KR, Blough BE, Brandt SD, Kavanagh PV, Partilla JS, Baumann MH (February 2016). "The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue". Neuropharmacology. 101: 68–75. doi:10.1016/j.neuropharm.2015.09.004. PMC   4681602 . PMID   26362361.
  29. 1 2 Sprague JE, Everman SL, Nichols DE (June 1998). "An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine". Neurotoxicology. 19 (3): 427–441. PMID   9621349.
  30. 1 2 Johnson MP, Huang XM, Nichols DE (December 1991). "Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue". Pharmacology, Biochemistry, and Behavior. 40 (4): 915–922. doi:10.1016/0091-3057(91)90106-c. PMID   1726189.
  31. 1 2 Johnson MP, Nichols DE (July 1991). "Combined administration of a non-neurotoxic 3,4-methylenedioxymethamphetamine analogue with amphetamine produces serotonin neurotoxicity in rats". Neuropharmacology. 30 (7): 819–822. doi:10.1016/0028-3908(91)90192-e. PMID   1717873.
  32. ↑ Nichols DE, Brewster WK, Johnson MP, Oberlender R, Riggs RM (February 1990). "Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA)". J Med Chem. 33 (2): 703–710. doi:10.1021/jm00164a037. PMID   1967651.
  33. ↑ Oberlender R, Nichols DE (December 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". J Pharmacol Exp Ther. 255 (3): 1098–1106. doi:10.1016/S0022-3565(25)22947-0. PMID   1979813.
  34. ↑ Nichols DE, Johnson MP, Oberlender R (January 1991). "5-Iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine". Pharmacol Biochem Behav. 38 (1): 135–139. doi:10.1016/0091-3057(91)90601-w. PMID   1826785.
  35. ↑ Johnson MP, Frescas SP, Oberlender R, Nichols DE (May 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)". J Med Chem. 34 (5): 1662–1668. doi:10.1021/jm00109a020. PMID   1674539.
  36. ↑ Marona-Lewicka D, Nichols DE (June 1994). "Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan". Eur J Pharmacol. 258 (1–2): 1–13. doi:10.1016/0014-2999(94)90051-5. PMID   7925587.
  37. 1 2 3 Cozzi NV, Frescas S, Marona-Lewicka D, Huang X, Nichols DE (March 1998). "Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential". Pharmacol Biochem Behav. 59 (3): 709–715. doi:10.1016/s0091-3057(97)00557-1. PMID   9512076.
  38. 1 2 WO 2022/032147,Baggott M,"2-Aminoindane compounds for mental disorders or enhancement.",published 10 February 2022, assigned to Tactogen Inc.
  39. ↑ Nichols DE, Weintraub HJ, Pfister WR, Yim GK (1978). "The Use of Rigid Analogues to Probe Hallucinogen Receptors". QuaSAR, Quantitative Structure Activity Relationships of Analgesics, Narcotic Antagonists, and Hallucinogens. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration. pp. 70–83.
  40. ↑ Nichols DE, Barfknecht CF, Long JP, Standridge RT, Howell HG, Partyka RA, Dyer DC (February 1974). "Potential psychotomimetics. 2. Rigid analogs of 2,5-dimethoxy-4-methylphenylisopropylamine (DOM, STP)". J Med Chem. 17 (2): 161–166. doi:10.1021/jm00248a004. PMID   4809251.
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