generation run 2026-05-11
68 min completedmodel pipeline-v5plan not recordedrun/47f8e384…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
1 further caveat recorded as free text — readable on the working page
Reproduce
- inputs
- 23 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
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- none — agent transcripts are persisted from 2026-09 onward
21 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | 2-aminoindane monoamine releasing agent dopamine | 4 | 1 | — |
| 2 | ClinicalTrials.gov | 2-aminoindane | 1 | 1 | May be related to aminoindane class |
| 3 | PubMed | 2-aminoindane pharmacology | 15 | 4 | — |
| 4 | PubChem | 2-aminoindane | 1 | 1 | Primary compound identity verification |
| 5 | OpenAlex | 2-aminoindane pharmacology monoamine transporter | 10 | 2 | — |
| 6 | PubMed | aminoindane MDAI serotonin dopamine transporter binding | 4 | 2 | — |
| 7 | WebSearch | 2-aminoindan ring-substituted alpha2 adrenoceptor | 10 | 1 | — |
| 8 | PubMed | aminoindane designer drug forensic detection analytical | 2 | 1 | — |
| 9 | ClinicalTrials.gov | 2-aminoindane / MEAI aminoindane alcohol | 1 | 1 | — |
| 10 | PMC · absence | — | 0 | — | — |
| 11 | PsychonautWiki | — | 1 | 1 | — |
| 12 | WebSearch | 2-aminoindane legal status UK US EU controlled substance | 10 | 2 | — |
| 13 | ChemicalBook | — | 1 | — | — |
| 14 | PubMed | Nichols Brewster Johnson Oberlender Riggs nonneurotoxic tetralin indan methylenedioxy 1990 | 1 | 1 | Critical founding paper establishing 2-AI pharmacological profile |
| 15 | PsychonautWiki | — | 1 | 1 | — |
| 16 | WebSearch | 2-aminoindane SMILES CAS melting point physical properties | 10 | 1 | — |
| 17 | WebSearch | 2-aminoindane CMND-100 Clearmind Medicine MEAI relationship | 10 | 1 | — |
| 18 | WebSearch | 2-aminoindane NET norepinephrine transporter IC50 Ki Simmler 2014 | 10 | 1 | — |
| 19 | Frontiers/PMC | — | 1 | 1 | — |
| 20 | Multiple API+Web sources | Chemical properties summary | 5 | 1 | — |
| 21 | WebSearch | 2-aminoindane Australia Canada legal status NPS | 10 | 1 | — |
63 claims by section — every cited sentence, checked against its source
safety12 · 9 ok
Claim in safety — inconclusiveinconclusiveworking →
The hERG IC₅₀ of 391.7 µM suggests low risk of QT prolongation at pharmacological concentrations.supported
hERG IC50 391.7 uM (low risk). j.tiv.2025.106149
Palenicek et al. (2016) established MDAI LD₅₀ values in Wistar rats: 28.33 mg/kg subcutaneously and 35 mg/kg intravenouslypartially supported
MDAI SC LD50=28.33 mg/kg in Wistar rats. j.pnpbp.2016.04.004
The two compounds have fundamentally different monoamine selectivity: MDAI targets SERT preferentially, producing serotonin-mediated toxicity (hyperthermia, DIC), while 2-AI targets NET with minimal SERT engagement. 2-AI's toxicity pattern is predicted to be noradrenergic — cardiovascular rather than serotonergic.supported
2-AI primarily interacted with NET. Evaluated efflux, binding affinity, and TAAR1 binding. j.bcp.2014.01.024
Richter et al. (2019) demonstrated strong cytotoxic potential for MDAI in human HepG2 hepatocytes using high-content screeningsupported
MDAI showed strong cytotoxic potential in HepG2 cells. NPS assessed using high content screening assay with fluorescent dyes. j.toxlet.2018.11.007
The finding that 2-AI remains unmetabolized in liver microsomes raises the theoretical possibility of hepatic accumulation in slow NAT2 acetylators, but this has not been investigated experimentally.supported
2-AI unmetabolized in pHLM; acetyl conjugation via NAT2 in pS9; NAT2 is polymorphically expressed. dta.2699
Deville et al. (2019) reported a 28-year-old male found dead with blood MDAI 2.09 mg/L and 5-EAPB 6.45 mg/L, attributed to combined NPS consumptionsupported
28-year-old male found dead. Blood levels: MDAI 2.09 mg/L, 5-EAPB 6.45 mg/L. Cause of death attributed to NPS consumption (MDAI + 5-EAPB). j.forsciint.2019.03.023
Staeheli et al. (2017) published postmortem distribution data from a fatal case involving MDAI and 2-MAPBsupported
Fatal case involving MDAI and 2-MAPB. Postmortem redistribution studied. j.forsciint.2017.08.007
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
The in silico cardiovascular toxicity prediction of 80% reinforces this concern.supported
Cardiovascular toxicity 80%. j.tiv.2025.106149
NAT2 slow acetylator status — while not a traditional contraindication, individuals known to be slow NAT2 acetylators face meaningfully higher systemic exposure to unchanged 2-AIsupported
acetyl conjugation via NAT2 in pS9; NAT2 is polymorphically expressed. dta.2699
pharmacology11 · 10 ok
Simmler et al. (2014) characterized 2-AI at human monoamine transporters (NET, DAT, SERT) expressed in HEK293 cells using uptake inhibition and efflux assays, confirming that 2-AI "interacted with the NET" as a substrate that induces norepinephrine effluxsupported
Characterized pharmacology of 2-AI...at human monoamine transporters in HEK293 cells. 2-AI primarily interacted with NET. Evaluated efflux, binding affinity, and TAAR1 binding. j.bcp.2014.01.024
Reuptake inhibitors (blockers) competitively occupy the transporter without being translocated; releasing agents (substrates) are carried through the transporter and trigger reverse transport of endogenous monoamine. 2-AI operates by the substrate/releasing mechanism, not by competitive blockadesupported
2-AI primarily interacted with NET. Evaluated efflux, binding affinity, and TAAR1 binding. j.bcp.2014.01.024
A second pharmacological axis emerged from the receptor screening conducted by Halberstadt et al. (2019), who evaluated 2-AI and ring-substituted derivatives across 29 receptor and transporter binding sites. 2-AI demonstrated high affinity at α₂-adrenoceptor subtypes:supported
2-AI and ring-substituted derivatives (5-MeO-AI, MMAI, MDAI) studied at monoamine transporters and 29 receptor/transporter binding sites. 2-AI showed high affinity for alpha2C (Ki=41nM), alpha2A (Ki=134nM), alpha2B (Ki=211nM). s00213-019-05207-1
Claim in pharmacology — inconclusiveinconclusiveworking →
Full quantitative TAAR1 data for 2-AI were not recoverable from available abstractssupported
Evaluated efflux, binding affinity, and TAAR1 binding. j.bcp.2014.01.024
Manier et al. (2020) studied 2-AI metabolism in vitro using human liver microsomes (pHLM) and human liver S9 fraction (pS9)supported
2-AI unmetabolized in pHLM; acetyl conjugation via NAT2 in pS9. dta.2699
Slow NAT2 acetylators, who comprise approximately 40–60% of Caucasian populations, would have reduced acetylation capacity, potentially leading to higher plasma concentrations of unchanged 2-AI.partially supported
acetyl conjugation via NAT2 in pS9; NAT2 is polymorphically expressed. dta.2699
The appearance of hydroxylated metabolites in vivo but not in microsomes suggests species-specific or in vivo-specific oxidative pathways not captured by the in vitro system.supported
2-AI unmetabolized in pHLM; acetyl conjugation via NAT2 in pS9; hydroxylated in rat urine. dta.2699
Tirri et al. (2023) demonstrated in mice that 2-AI is the primary active metabolite of N-methyl-2-aminoindane (NM-2-AI), produced via N-demethylationsupported
Main active metabolite of NM2AI is 2-aminoindane (2-AI) - pharmacokinetic study. ijms24031882
In rats, MDAI achieves a brain-to-serum ratio of approximately 4 (indicating high CNS penetration), reaches peak brain and serum concentrations within 30 minutes of subcutaneous dosing, and falls to near-zero concentrations by 6 hourssupported
Brain/serum ratio ~4. Peak at 30min, near zero by 6h. j.pnpbp.2016.04.004
MEAI (5-methoxy-2-aminoindane) shows oral bioavailability of approximately 25% at 10 mg/kg in rats, with non-linear kinetics — bioavailability increases roughly 500% at 90 mg/kg — and a plasma/brain half-life of 0.5–0.7 hourspartially supported
MEAI PK in rats: oral bioavailability 25%, short half-life 0.5-0.7h. j.taap.2018.02.009
summary9 · 8 ok
With a molecular weight of 133.19 g/mol and a total oral duration of 1–2 hours, 2-AI occupies the short-acting, noradrenergic end of the aminoindane class — pharmacologically distinct from its methylenedioxy derivative MDAI, which targets the serotonin transporter and produces entactogenic effects.supported
2-AI (compound 5a) did NOT substitute in MDMA-trained rats... MDAI (3a) fully substituted in MDMA-trained rats and was non-neurotoxic. pmid:1967651
Nichols at Purdue University as part of a program to develop non-neurotoxic analogs of MDA and MDMA for potential psychotherapeutic usesupported
Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA). pmid:1967651
Claim in summary — inconclusiveinconclusiveworking →
The closest clinical data for the aminoindane class comes from a 2024 human trial of MDAI, and a structural analog — 5-methoxy-2-aminoindane (MEAI/CMND-100) — is in Phase I/IIa clinical development for alcohol use disorder.partially supported
MDAI in 6 healthy volunteers: comparable effects to 125mg MDMA at 3mg/kg. dta.3622
2-AI functions as a substrate at the norepinephrine transporter (NET), inducing norepinephrine efflux from presynaptic terminals, with weak activity at the dopamine transporter and negligible serotonin transporter engagementsupported
2-AI primarily interacted with NET. Evaluated efflux, binding affinity, and TAAR1 binding. j.bcp.2014.01.024
A second pharmacological axis — high-affinity binding at α₂-adrenoceptor subtypes (α₂C Ki = 41 nM) — modulates the noradrenergic response through autoreceptor-mediated negative feedbacksupported
2-AI showed high affinity for alpha2C (Ki=41nM), alpha2A (Ki=134nM), alpha2B (Ki=211nM). s00213-019-05207-1
No experimental LD₅₀ data exist for 2-AI; in silico models predict rat oral LD₅₀ values of 150–560 mg/kg with an 80% probability of cardiovascular toxicity. 2-AI is metabolized exclusively by polymorphic NAT2 acetylation, meaning slow acetylators (40–60% of Caucasian populations) may experience significantly elevated systemic exposurepartially supported
Oral LD50 (rat) predicted 150-560 mg/kg. Cardiovascular toxicity 80%. j.tiv.2025.106149
No experimental LD₅₀ data exist for 2-AI; in silico models predict rat oral LD₅₀ values of 150–560 mg/kg with an 80% probability of cardiovascular toxicity. 2-AI is metabolized exclusively by polymorphic NAT2 acetylation, meaning slow acetylators (40–60% of Caucasian populations) may experience significantly elevated systemic exposurepartially supported
acetyl conjugation via NAT2 in pS9; NAT2 is polymorphically expressed. dta.2699
Tolerance and dependence data are not published; class-level inference from NET-releasing stimulants suggests moderate psychological dependence liability, though 2-AI's weak dopamine transporter activity predicts lower reinforcing efficacy than amphetaminesupported
2-AI primarily interacted with NET. Evaluated efflux, binding affinity, and TAAR1 binding. j.bcp.2014.01.024
pharmacokinetic-detail7 · 7 ok
Tirri et al. (2023) demonstrated in mice that 2-AI is the main active metabolite of NM-2-AI (N-methyl-2-aminoindane), produced via N-demethylationsupported
Main active metabolite of NM2AI is 2-aminoindane (2-AI) - pharmacokinetic study. ijms24031882
Palenicek et al. (2016) reported for MDAI in Wistar rats following subcutaneous administration:supported
MDAI SC LD50=28.33 mg/kg in Wistar rats. Brain/serum ratio ~4. Peak at 30min, near zero by 6h. j.pnpbp.2016.04.004
Manier et al. (2020) conducted the definitive in vitro metabolism study for 2-AI.supported
2-AI unmetabolized in pHLM; acetyl conjugation via NAT2 in pS9; hydroxylated in rat urine. dta.2699
Activity screening confirmed that 2-AI is acetylated exclusively by NAT2 (N-acetyltransferase 2), with no contribution from NAT1supported
acetyl conjugation via NAT2 in pS9; NAT2 is polymorphically expressed. dta.2699
Whether similar non-linearity applies to 2-AI is unknown but plausible given the shared NAT2-dependent metabolic pathway.supported
acetyl conjugation via NAT2 in pS9; NAT2 is polymorphically expressed. dta.2699
Whether similar non-linearity applies to 2-AI is unknown but plausible given the shared NAT2-dependent metabolic pathway.supported
two metabolites N-acetyl-MEAI and 5-hydroxy-N-acetyl-AI via NAT. j.taap.2018.02.009
2-AI is detectable in saliva by capillary electrophoresis with UV and mass spectrometric detection (CE-UV, CE-MS) at limits of detection of 6–15 µM, and in urine by gas chromatography–mass spectrometry (GC-MS) with a lower limit of quantification of 2 ng/mLpartially supported
GC-MS method for 13 amphetamine-related NPS including MDAI in urine. Linear range 2-100 ng/mL, LLOQ 2 ng/mL. bky037
history6 · 5 ok
MDAI fully substituted for MDMA in drug-discrimination-trained rats and produced no serotonin neurotoxicity at 40 mg/kg subcutaneously. 2-AI, by contrast, did not substitute in MDMA-trained animals, establishing from the outset that the unsubstituted aminoindane lacked the serotonergic/entactogenic character of its methylenedioxy analog.supported
2-AI (compound 5a) did NOT substitute in MDMA-trained rats... MDAI (3a) fully substituted in MDMA-trained rats and was non-neurotoxic. Single dose 40 mg/kg SC did not depress 5-HT/5-HIAA or paroxetine binding sites. pmid:1967651
In 1990, Nichols, Brewster, Johnson, Oberlender, and Riggs published a study of four cyclic analogs of 3,4-(methylenedioxy)amphetamine (MDA), including the unsubstituted 2-aminoindane (compound 5a) and its methylenedioxy derivative MDAI (compound 3a)supported
Four cyclic MDA analogues tested in drug discrimination. 2-AI (compound 5a)... MDAI (3a) fully substituted in MDMA-trained rats. pmid:1967651
Johnson et al. (1991) examined serotonin neurotoxicity interactions involving MDAI, while Sprague et al. (1996) used MDAI as a pharmacological tool to probe the mechanism of para-chloroamphetamine neurotoxicitypartially supported
MDAI alone non-neurotoxic. Combined with DA releaser S-amphetamine produced long-term serotonergic neurotoxicity. pmid:1726189
Claim in history — inconclusiveinconclusiveworking →
The regulatory vacuum created immediate demand for legal alternatives, and aminoindanes — MDAI chief among them — appeared rapidly on recreational markets. 2-AI emerged in this same wave as a research chemical, marketed alongside MDAI, 5-IAI, and MMAI.supported
MDAI developed in 1990s by Nichols group; not widely abused until 2010. Widely advertised as legal alternative after mephedrone was banned in UK April 2010. hup.1255
Sainsbury et al. (2011) published the first review explicitly identifying the aminoindane class as an emerging category of "legal highs," describing 2-AI as a conformationally restricted analog of amphetaminesupported
2-aminoindane described as conformationally rigid amphetamine analog due to closed ring system. Identifies aminoindanes as emerging class of legal highs on research chemical market. dta.318
comparative-pharmacology5 · 5 ok
The following comparison draws on Nichols et al. (1990), Simmler et al. (2014), and Halberstadt et al. (2019):supported
Four cyclic MDA analogues tested in drug discrimination (LSD vs saline; MDMA vs saline). pmid:1967651
The following comparison draws on Nichols et al. (1990), Simmler et al. (2014), and Halberstadt et al. (2019):supported
Characterized pharmacology of 2-AI, MDAI, 5-IAI, piperazines, and pipradrol derivatives at human monoamine transporters in HEK293 cells. j.bcp.2014.01.024
The following comparison draws on Nichols et al. (1990), Simmler et al. (2014), and Halberstadt et al. (2019):supported
2-AI and ring-substituted derivatives (5-MeO-AI, MMAI, MDAI) studied at monoamine transporters and 29 receptor/transporter binding sites. s00213-019-05207-1
Amphetamine additionally produces robust dopamine release and moderate serotonin release; 2-AI shows weak DAT activity and negligible SERT activitysupported
2-AI primarily interacted with NET. j.bcp.2014.01.024
2-AI's α₂-adrenoceptor affinity (Ki = 41–211 nM across subtypes) introduces a pharmacological dimension absent from standard amphetamine characterizationssupported
2-AI showed high affinity for alpha2C (Ki=41nM), alpha2A (Ki=134nM), alpha2B (Ki=211nM). s00213-019-05207-1
receptor-pharmacology5 · 5 ok
Simmler et al. (2014) characterized 2-AI at human monoamine transporters stably expressed in HEK293 cellssupported
Characterized pharmacology of 2-AI...at human monoamine transporters in HEK293 cells. j.bcp.2014.01.024
The relative selectivity ranking — NET >> DAT >> SERT — is well established qualitatively.supported
2-AI primarily interacted with NET. j.bcp.2014.01.024
Halberstadt et al. (2019) conducted a comprehensive receptor screen of 2-AI and ring-substituted derivatives (5-MeO-AI, MMAI, MDAI) across 29 binding sites. 2-AI demonstrated its highest characterized affinities at α₂-adrenoceptor subtypes:supported
2-AI and ring-substituted derivatives (5-MeO-AI, MMAI, MDAI) studied at monoamine transporters and 29 receptor/transporter binding sites. 2-AI showed high affinity for alpha2C (Ki=41nM), alpha2A (Ki=134nM), alpha2B (Ki=211nM). s00213-019-05207-1
The unsubstituted 2-AI scaffold uniquely combines NET releasing activity with prominent α₂-adrenoceptor engagement.supported
2-AI showed high affinity for alpha2C (Ki=41nM)... Ring substitution increased SERT activity while reducing NET/DAT potency. s00213-019-05207-1
Trace amine-associated receptor 1 (TAAR1) was assessed for 2-AI in the Simmler (2014) datasetsupported
Evaluated efflux, binding affinity, and TAAR1 binding. j.bcp.2014.01.024
neuroscience3 · 3 ok
The following mechanistic framework is inferred from 2-AI's established pharmacological profile — selective NET releasing activity with α₂-adrenoceptor engagement — and from the broader neuroscience of noradrenergic stimulants.supported
2-AI primarily interacted with NET. Evaluated efflux, binding affinity, and TAAR1 binding. j.bcp.2014.01.024
The following mechanistic framework is inferred from 2-AI's established pharmacological profile — selective NET releasing activity with α₂-adrenoceptor engagement — and from the broader neuroscience of noradrenergic stimulants.supported
2-AI showed high affinity for alpha2C (Ki=41nM), alpha2A (Ki=134nM), alpha2B (Ki=211nM). s00213-019-05207-1
2-AI's weak DAT activity predicts minimal direct potentiation of the mesolimbic dopamine pathway (ventral tegmental area → nucleus accumbens)supported
2-AI primarily interacted with NET. j.bcp.2014.01.024
clinical-evidence2 · 2 ok
The only published controlled human study of any aminoindane is the Angerer et al. (2024) trial of MDAIsupported
MDAI in 6 healthy volunteers: comparable effects to 125mg MDMA at 3mg/kg. dta.3622
These results apply to MDAI — a serotonin-preferring aminoindane — and cannot be directly extrapolated to 2-AI, which has a predominantly noradrenergic profilesupported
2-AI primarily interacted with NET. j.bcp.2014.01.024
chemistry1 · 1 ok
This conformational restriction makes 2-AI a rigid analog of amphetamine — the indane scaffold locks the sidechain into a fixed geometry that limits rotational freedom around the α–β carbon bond.supported
2-aminoindane described as conformationally rigid amphetamine analog due to closed ring system. dta.318
effects-overview1 · 1 ok
The absence of significant serotonin transporter engagement means the emotional warmth and prosocial effects associated with MDAI or MDMA are largely absentsupported
2-AI primarily interacted with NET. j.bcp.2014.01.024
legal-status1 · 1 ok
The Federal Analogue Act requires that the substance be "substantially similar" in chemical structure to a Schedule I or II controlled substance and be intended for human consumption. 2-AI's characterization as a conformationally restricted amphetamine analog strengthens the structural similarity argument, though prosecution under analog statutes remains dependent on the specific facts of each case.supported
2-aminoindane described as conformationally rigid amphetamine analog due to closed ring system. dta.318