MMAI

{{Short description|Chemical compound}}

{{Infobox drug

| IUPAC_name = 5-Methoxy-6-methyl-2,3-dihydro-1H-inden-2-amine

| image = 5-methoxy-6-methyl-2-aminoindane.svg

| width =

| tradename =

| pregnancy_category =

| legal_status = Uncontrolled

| routes_of_administration = By mouth

| class = Selective serotonin releasing agent; Entactogen

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 136468-19-4

| ATC_prefix = None

| ATC_suffix =

| PubChem = 131575

| ChemSpiderID = 116274

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = JF10U4I82P

| synonyms = MMAI; MMAi; 5-Methoxy-6-methyl-2-aminoindan

| C = 11 | H = 15 | N = 1 | O = 1

| SMILES = Cc1cc2CC(N)Cc2cc1OC

| StdInChI = 1S/C11H15NO/c1-7-3-8-4-10(12)5-9(8)6-11(7)13-2/h3,6,10H,4-5,12H2,1-2H3

| StdInChIKey = JLESVLCTIOAHPT-UHFFFAOYSA-N

}}

5-Methoxy-6-methyl-2-aminoindane (MMAI) is a drug of the 2-aminoindane group developed in the 1990s by a team led by David E. Nichols at Purdue University.{{cite journal | vauthors = Marona-Lewicka D, Nichols DE | title = Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan | journal = European Journal of Pharmacology | volume = 258 | issue = 1–2 | pages = 1–13 | date = June 1994 | pmid = 7925587 | doi = 10.1016/0014-2999(94)90051-5 | citeseerx = 10.1.1.688.1895 }} It acts as a less neurotoxic and highly selective serotonin releasing agent (SSRA) and produces entactogenic effects in humans.{{cite journal | vauthors = Li Q, Murakami I, Stall S, Levy AD, Brownfield MS, Nichols DE, Van de Kar LD | title = Neuroendocrine pharmacology of three serotonin releasers: 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAi) and p-methylthioamphetamine (MTA) | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 279 | issue = 3 | pages = 1261–1267 | date = December 1996 | doi = 10.1016/S0022-3565(25)21285-X | pmid = 8968349 }}{{cite journal | vauthors = Rudnick G, Wall SC | title = Non-neurotoxic amphetamine derivatives release serotonin through serotonin transporters | journal = Molecular Pharmacology | volume = 43 | issue = 2 | pages = 271–276 | date = February 1993 | doi = 10.1016/S0026-895X(25)13609-2 | pmid = 8429828 }}{{cite journal | vauthors = Luethi D, Kolaczynska KE, Docci L, Krähenbühl S, Hoener MC, Liechti ME | title = Pharmacological profile of mephedrone analogs and related new psychoactive substances | journal = Neuropharmacology | volume = 134 | issue = Pt A | pages = 4–12 | date = May 2018 | pmid = 28755886 | doi = 10.1016/j.neuropharm.2017.07.026 | s2cid = 28786127 | url = https://edoc.unibas.ch/57357/1/20170920120908_59c23e44b5f0e.pdf }} It has been sold as a designer drug and research chemical online since 2010.

The drug is one of the only known monoamine releasing agents (MRAs) with greater than 100-fold selectivity for the serotonin transporter (SERT) over the dopamine transporter (DAT).{{cite journal | vauthors = Rudin D, Liechti ME, Luethi D | title = Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics | journal = Exp Neurol | volume = 343 | issue = | pages = 113778 | date = September 2021 | pmid = 34090893 | doi = 10.1016/j.expneurol.2021.113778 | url = | doi-access = free }} Receptor interaction data for MMAI have also been reported.{{cite journal | vauthors = Luethi D, Kolaczynska KE, Docci L, Krähenbühl S, Hoener MC, Liechti ME | title = Pharmacological profile of mephedrone analogs and related new psychoactive substances | journal = Neuropharmacology | volume = 134 | issue = Pt A | pages = 4–12 | date = May 2018 | pmid = 28755886 | doi = 10.1016/j.neuropharm.2017.07.026 | url = }}

MMAI has been shown to relieve stress-induced depression in rats more robustly than sertraline,{{cite journal | vauthors = Marona-Lewicka D, Nichols DE | title = The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats | journal = Stress | volume = 2 | issue = 2 | pages = 91–100 | date = December 1997 | pmid = 9787258 | doi = 10.3109/10253899709014740 }} and as a result it has been suggested that SSRAs like MMAI and 4-methylthioamphetamine (4-MTA) could be developed as novel antidepressants with a faster onset of therapeutic action and superior effectiveness to current antidepressants such as the selective serotonin reuptake inhibitors (SSRIs).{{cite journal | vauthors = Scorza C, Silveira R, Nichols DE, Reyes-Parada M | title = Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action | journal = Neuropharmacology | volume = 38 | issue = 7 | pages = 1055–1061 | date = July 1999 | pmid = 10428424 | doi = 10.1016/S0028-3908(99)00023-4 | s2cid = 13714807 }}

MMAI alone does not appear to produce serotonergic neurotoxicity with either acute or chronic administration in animals.{{cite journal | vauthors = Johnson MP, Nichols DE | title = Combined administration of a non-neurotoxic 3,4-methylenedioxymethamphetamine analogue with amphetamine produces serotonin neurotoxicity in rats | journal = Neuropharmacology | volume = 30 | issue = 7 | pages = 819–822 | date = July 1991 | pmid = 1717873 | doi = 10.1016/0028-3908(91)90192-e | url = }}{{cite journal | vauthors = Johnson MP, Conarty PF, Nichols DE | title = [3H]monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues | journal = Eur J Pharmacol | volume = 200 | issue = 1 | pages = 9–16 | date = July 1991 | pmid = 1685125 | doi = 10.1016/0014-2999(91)90659-e | url = }} However, subsequent research found that a single high dose of MMAI could produce significant serotonergic neurotoxicity. In addition, combination of MMAI with the dopamine releasing agent dextroamphetamine has been found to produce dose-dependent serotonergic neurotoxicity in animals. Hence, MMAI is not a fully non-neurotoxic MDMA analogue.

MMAI is the 2-aminoindane analogue of 3-methoxy-4-methylamphetamine (MMA).{{cite journal | vauthors = Nichols DE, Marona-Lewicka D, Huang X, Johnson MP | title = Novel serotonergic agents | journal = Drug des Discov | volume = 9 | issue = 3–4 | pages = 299–312 | date = 1993 | pmid = 8400010 | doi = | url = https://bitnest.netfirms.com/external/DrugDes.Disc/9.299 }}

class="wikitable" style="font-size:small;" |+ {{Nowrap|Activities of 2-aminoindanes and amphetamine relatives}}
rowspan="2" | Compound	colspan="3" | Monoamine release ({{Abbrlink|EC50|half-maximal effective concentration}}, nM) || rowspan="2" | Ref
Serotonin	Norepinephrine	Dopamine
2-AI	>10,000	86	439
MDAI	114	117	1,334
MMAI	31	3,101	>10,000
MEAI	134	861	2,646
d-Amphetamine	698–1,765	6.6–7.2	5.8–24.8	{{cite journal | vauthors = 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 | title = Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products | journal = Neuropsychopharmacology | volume = 38 | issue = 4 | pages = 552–562 | date = March 2013 | pmid = 23072836 | pmc = 3572453 | doi = 10.1038/npp.2012.204 }}{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken [NJ] | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}{{cite book | vauthors = Glennon RA, Dukat M | title = Neuropharmacology of New Psychoactive Substances (NPS) | chapter = Structure-Activity Relationships of Synthetic Cathinones | series = Current Topics in Behavioral Neurosciences | volume = 32 | issue = | pages = 19–47 | date = 2017 | pmid = 27830576 | pmc = 5818155 | doi = 10.1007/7854_2016_41 | isbn = 978-3-319-52442-9 | chapter-url = }}{{cite book | vauthors = Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB | chapter = Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes | title = Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc | series = NIDA Res Monogr | volume = 180 | pages = 1–476 (252) | date = 1999 | pmid = 11680410 | doi = | url = https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261 | quote = 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). [...] }}
MDA	160–162	47–108	106–190
MDMA	50–85	54–110	51–278	{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | s2cid = 15573624 }}{{cite journal | vauthors = Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV | title = The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue | journal = Neuropsychopharmacology | volume = 37 | issue = 5 | pages = 1192–1203 | date = April 2012 | pmid = 22169943 | pmc = 3306880 | doi = 10.1038/npp.2011.304 }}{{cite journal | vauthors = Marusich JA, Antonazzo KR, Blough BE, Brandt SD, Kavanagh PV, Partilla JS, Baumann MH | title = The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue | journal = Neuropharmacology | volume = 101 | pages = 68–75 | date = February 2016 | pmid = 26362361 | pmc = 4681602 | doi = 10.1016/j.neuropharm.2015.09.004 }}{{cite journal | vauthors = Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL | title = 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro | journal = Molecular Pharmacology | volume = 63 | issue = 6 | pages = 1223–1229 | date = June 2003 | pmid = 12761331 | doi = 10.1124/mol.63.6.1223 | s2cid = 839426 }}{{cite journal | vauthors = Brandt SD, Walters HM, Partilla JS, Blough BE, Kavanagh PV, Baumann MH | title = The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats | journal = Psychopharmacology (Berl) | volume = 237 | issue = 12 | pages = 3703–3714 | date = December 2020 | pmid = 32875347 | doi = 10.1007/s00213-020-05648-z | url = | pmc = 7686291 }}
3-MA	{{Abbr|ND|No data}}	58.0	103
class="sortbottom" | colspan="5" style="width: 1px; background-color:#eaecf0; text-align: center;" | 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: {{cite journal | vauthors = Halberstadt AL, Brandt SD, Walther D, Baumann MH | title = 2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors | journal = Psychopharmacology (Berl) | volume = 236 | issue = 3 | pages = 989–999 | date = March 2019 | pmid = 30904940 | pmc = 6848746 | doi = 10.1007/s00213-019-05207-1 | url = }}