Objectives: Aminoindanes ("bath salts," a class of novel psychoactive substances, NPSs) increased rapidly in popularity on the recreational drug market, particularly after mephedrone and other synthetic cathinones were banned in the UK in 2010. Novel aminoindanes continue to emerge, but relatively little is known about their effects and risks. Their history, chemistry, pharmacology, behavioral effects, pharmacokinetics, and toxicity are reviewed in this paper. Methods: Scientific literature was searched on ISI Web of Knowledge: Web of Science (WoS) during June and July 2017, using English language terms: aminoindanes such as 5,6-methylenedioxy-2-aminoindane (MDAI), 5-iodo-2-aminoindane (5-IAI), 2-aminoindane (2-AI), 5,6-methylenedioxy-N-methyl-2-aminoindane (MDMAI), and 5-methoxy-6-methyl-2-aminoindane (MMAI). WoS was selected as it searches several databases simultaneously and has quality criteria for inclusion. For typical use and effects, Erowid, PsychonautWiki, Bluelight, and Drugs-Forum were searched; for legal status and epidemiology, the European Information System and Database on New Drugs (EDND) was used. Results: Aminoindanes were first synthesized for medical use, e.g., as anti-Parkinsonian drugs and later as a potential compound facilitating psychotherapy; however, they are now widely substituted for ecstasy. Their mechanisms of action (primarily via serotonin) mean that they may pose a significant risk of serotonin syndrome at high doses or when combined with other drugs. Fatally toxic effects have been observed both in the laboratory in animal studies and in clinic, where deaths related with aminoindanes have been reported. Conclusion: Greater knowledge about aminoindanes is urgently required to decrease risks of fatal intoxication, and appropriate legislation is needed to protect public health without impeding research.
- Publication type
- Journal Article MeSH
- Review MeSH
- MeSH
- Acute Disease therapy MeSH
- Chlorpromazine MeSH
- Diazepam MeSH
- Haloperidol MeSH
- Humans MeSH
- Neuroleptic Malignant Syndrome MeSH
- N-Methyl-3,4-methylenedioxyamphetamine * pharmacology chemistry adverse effects MeSH
- Substance-Related Disorders * drug therapy MeSH
- First Aid methods MeSH
- Serotonin Syndrome drug therapy MeSH
- Toxicology MeSH
- Illicit Drugs * MeSH
- Legislation as Topic MeSH
- Check Tag
- Humans MeSH
1. 5,6-Methylenedioxy-2-aminoindane (MDAI) is a member of aminoindane drug family with serotoninergic effect, which appeared on illicit drug market as a substitute for banned stimulating and entactogenic drugs. 2. Metabolism of MDAI, which has been hitherto unexplored, was studied in rats dosed with a subcutaneous dose of 20 mg MDAI.HCl/kg body weight. The urine of rats was collected within 24 h after dosing for analyses by HPLC-ESI-HRMS and GC/MS. 3. The main metabolic pathways proceeding in parallel were found to be oxidative demethylenation followed by O-methylation and N-acetylation. These pathways gave rise to five metabolites, namely, 5,6-dihydroxy-2-aminoindane, 5-hydroxy-6-methoxy-2-aminoindane, N-acetyl-5,6-methylenedioxy-2-aminoindane, N-acetyl-5,6-dihydroxy-2-aminoindane and N-acetyl-5-hydroxy-6-methoxy-2-aminoindane, which were found predominantly in the form of corresponding glucuronides and sulphates. However, the main portion of administered MDAI was excreted unchanged. 4. Minor metabolites formed primarily by hydroxylation at various sites include cis- and trans-1-hydroxy-5,6-methylenedioxy-2-aminoindane, 5,6-methylenedioxyindan-2-ol and 4-hydroxy-5,6-methylenedioxy-2-aminoindane. 5. Identification of all metabolites except for glucuronides, sulphates and tentatively identified 4-hydroxy-5,6-methylenedioxy-2-aminoindane was supported by synthesised reference standards.
MDAI (5,6-Methylenedioxy-2-aminoindane) has a reputation as a non-neurotoxic ecstasy replacement amongst recreational users, however the drug has been implicated in some severe and lethal intoxications. Due to this, and the fact that the drug is almost unexplored scientifically we investigated a broad range of effects of acute MDAI administration: pharmacokinetics (in sera, brain, liver and lung); behaviour (open field; prepulse inhibition, PPI); acute effects on thermoregulation (in group-/individually-housed rats); and systemic toxicity (median lethal dose, LD50) in Wistar rats. Pharmacokinetics of MDAI was rapid, maximum median concentration in serum and brain was attained 30min and almost returned to zero 6h after subcutaneous (sc.) administration of 10mg/kg MDAI; brain/serum ratio was ~4. MDAI particularly accumulated in lung tissue. In the open field, MDAI (5, 10, 20 and 40mg/kg sc.) increased exploratory activity, induced signs of behavioural serotonin syndrome and reduced locomotor habituation, although by 60min some effects had diminished. All doses of MDAI significantly disrupted PPI and the effect was present during the onset of its action as well as 60min after treatment. Unexpectedly, 40mg/kg MDAI killed 90% of animals in the first behavioural test, hence LD50 tests were conducted which yielded 28.33mg/kg sc. and 35mg/kg intravenous but was not established up to 40mg/kg after gastric administration. Disseminated intravascular coagulopathy (DIC) with brain oedema was concluded as a direct cause of death in sc. treated animals. Finally, MDAI (10, 20mg/kg sc.) caused hyperthermia and perspiration in group-housed rats. In conclusion, the drug had fast pharmacokinetics and accumulated in lipohilic tissues. Behavioural findings were consistent with mild, transient stimulation with anxiolysis and disruption of sensorimotor processing. Together with hyperthermia, the drug had a similar profile to related entactogens, especially 3,4-metyhlenedioxymethamphetamine (MDMA, ecstasy) and paramethoxymethamphetamine (PMMA). Surprisingly subcutaneous MDAI appears to be more lethal than previously thought and its serotonergic toxicity is likely exacerbated by group housing conditions. MDAI therefore poses greater risks to physical and mental health than recognised hitherto.
- MeSH
- Habituation, Psychophysiologic drug effects MeSH
- Indans administration & dosage pharmacokinetics pharmacology toxicity MeSH
- Lethal Dose 50 MeSH
- Brain drug effects MeSH
- Myocardium pathology MeSH
- Sweating drug effects MeSH
- Motor Activity drug effects MeSH
- Rats, Wistar MeSH
- Prepulse Inhibition drug effects MeSH
- Psychotropic Drugs administration & dosage pharmacokinetics pharmacology toxicity MeSH
- Serotonin Syndrome chemically induced MeSH
- Saliva drug effects MeSH
- Heart drug effects MeSH
- Body Temperature Regulation drug effects MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Smyslem této studie bylo zhodnotit behaviorální účinky vybraných nových syntetických drog (NSD) a jejich vliv na termoregulaci v ammálnim modelu. Měřili jsme lokomoční aktivitu zvířat, senzorimotorické zpracování informací a změnu tělesné teploty (za podmínky. kdy byla zvířata izolována, a za podmínky, kdy byla ve skupinách). Testované substance byly mefedron, methylon, 5,6-methylendioxy-2-aminoindan (MDAI) a para-methoxymetamfetamin (PMMA). Všechny substance měly stimulační účinky, narušovaly senzorimotorické zpracování informací a indukovaly hypertermii (výrazněji u zvířat ve skupinách). Nejúčinnějším simulantem byla droga mefedron. MDAI a PMMA pak nejvýrazněji narušovaly senzorimotorické zpracování informací. Poslední dvě zmíněné substance také nejvíce zvyšovaly tělesnou teplotu. Nejméně potentní substancí byla droga methylon.
The purpose of this study was to elucidate behavioral effects and the effects on thermoregulation of selected new synthetic drugs (NSD) in animal model. Locomotor activity, sensorimotor gating and change in body temperature (under isolated and crowded conditions) were evalua- ted. The compounds tested were: mephedrone, methylone, 5,6-methyle- nedioxy-2-aminoindane (MDAI) and para-methoxymethamphetamine (PMMA). All NSD had stimulatory effects, disrupted sensorimotor gating and induced hyperthermia (more pronounced under crowded condition). Mephedrone was the most powerful stimulant. On the contrary MDAI and PMMA were the most potent in disrupting sensorimotor gating and in inducing hyperthermia. Methylon had the lowest potency.
- Publication type
- Meeting Abstract MeSH
Ladostigil, (N-propargyl-(3R)-aminoindan-5-yl-ethyl-methyl karbamát) byl připraven jako potenciální léčivo Alzheimerovy nemoci tak, aby kombinoval neuroprotekční účinek rasagilinu s anticholinesterázovou aktivitou rivastigminu. Ladostigil je nový typ bifunkčního léčiva, tere kombinuje lék proti Parkinsonově nemoci s lékem proti Alzheimerově nemoci. Podrobnější studie farmakologického profilu dále ukázaly, že ladostigil má navíc i neuroprotektivní a antioxidační účinky, lze tedy na něj pohlížet jako na léčivo ovlivňující i více cílů než jen MAO-B a acetylcholinesterázu (tzv. multitargeted drug). Toto léčivo bylo vyvinuto k terapii komorbidity demence s parkinsonismem, protože kolem 40 % dementních pacientů trpí oběma chorobami. Již byla zahájena druhá fáze klinických zkoušek k vyhodnocení bezpečnosti a účinnosti u pacicientů s diagnózou mírné kognitivní poruchy (MCI).
Ladostigil, (N-propargyl-aminoindan-5-yl-ethyl-methyl carbamate) has been prepared in order to combine the neuroprotective effe cts of rasagiline, a selective inhibitor of monoamine oxidase-B with the cholinesterase inhibitory activity of rivastigmine as a poten tial treatment for Alzheimer‘s disease. Further studies of pharmacological profile revealed that ladostigil possesses neuroprotective and anti oxidant properties, therefore can be described as multitargeted drug. This drug was developed for the treatment of comorbidity of dementia with Parkinsonism, since approximately 40% of dementia patients suffer from both diseases. The Phase 2 of clinical trial to evaluate th e safety and efficacy of patients diagnosed with mild cognitive impairment (MCI) has been commencement.
- Keywords
- bifunkční léčivo, inhibitor MAO B, mírná kognitivní porucha,
- MeSH
- Alzheimer Disease * diagnosis drug therapy MeSH
- Cholinesterase Inhibitors administration & dosage therapeutic use MeSH
- Molecular Mechanisms of Pharmacological Action MeSH
- Drug Evaluation MeSH
- Clinical Trials as Topic MeSH
- Cognition Disorders diagnosis drug therapy MeSH
- Rats MeSH
- Humans MeSH
- Neuroprotective Agents * therapeutic use MeSH
- Memory Disorders prevention & control MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Antagonists of group I of metabotropic glutamate receptors (mGluRs) exhibit anticonvulsant as well as anxiolytic action in adult rodents. Therefore, we started to study these effects in developing rats. Motor seizures induced by pentylenetetrazol (PTZ) and cortical epileptic afterdischarges (CxADs) elicited by electrical stimulation were used in immature rats. High doses of antagonists were needed to demonstrate anticonvulsant effects. Antagonist of mGluR1 AIDA [(R,S)-1-aminoindan-1,5-dicarboxylic acid] suppressed the tonic phase of PTZ-induced generalized tonic-clonic seizures in 7-, 12-, and 18-day-old rats, but not in 25-day-old rats. No significant effect of AIDA against CxADs was found. Antagonists of mGluR5-MPEP [2-methyl-6-(phenylethynyl)-pyridine] and MTEP [3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine] exhibited the same effect against PTZ-induced seizures as AIDA. In addition, they exhibited an anticonvulsant action against CxADs in 12- and 18-day-old rats. No drug compromised motor performance. Anxiolytic action of all three antagonists was demonstrated in light/dark box or in elevated plus maze tests. Homing reaction was used as an age-appropriate test of learning. AIDA did not affect homing, whereas the highest dose of MPEP compromised this behavior in 12- and partially in 18-day-old rats. The three antagonists possess age-dependent anticonvulsant as well as anxiolytic action, with minimal negative side effects.
- MeSH
- Anticonvulsants pharmacology MeSH
- Anti-Anxiety Agents pharmacology MeSH
- Electric Stimulation MeSH
- Epilepsy chemically induced drug therapy MeSH
- Indans pharmacology therapeutic use MeSH
- Rats MeSH
- Psychomotor Performance drug effects MeSH
- Pyridines pharmacology therapeutic use MeSH
- Receptors, Metabotropic Glutamate antagonists & inhibitors MeSH
- Thiazoles pharmacology therapeutic use MeSH
- Age Factors MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
