479 ., and et al yst’s Laboratory, . drew attention They included 5, ., Monte . also found this to et al [3] cell cultures, and thus Drug Testing Drug Analysis and et al et al in vitro partment of Forensic Science and Drug Extensive investigations using animal and [5] . showed that MMAI would be relatively By contrast, the aminoindanes seem to Published online in Wiley Online Library: 11 July 2011 a . all conclude that whilst MMAI, MDAI, and et al [6,7] . Drug discrimination studies use animals that [4] et al more recent research points to the aminoindanes as [2] ane (5-IAI), and 5-methoxy-6-methyl-2-aminoindane L.A. King b Correspondence to: R.A. Braithwaite, De Monitoring, Franklin-Wilkins Building, King’sE-mail: College [email protected] London, SE1 9NH, UK. Department of ForensicBuilding, King’s College London, Science SE1 9 NH, and UK. Drug Monitoring,Kingston University, Franklin-Wilkins Surrey, UK;Longuee futur Rue St. address: Martin’s, Guernsey, States GY4 6LD, Anal UK advertising 5,6-methylenedioxy-2-aminoindane (MDAI), 5, ∗ a b to several rigidfor analogues MDMA that in had drug been discrimination found studies. to substitute having potent effects on serotonin releaseber and of re-uptake. A studies num- undertaken incerning the Ecstasy late (3,4-methylenedioxymethamphetamine; 1980s MDMA) andalso early 1990s included con- a comparison withthat a incorporated number an of indane MDMA ring. analogues Johnson be relatively benign at recreationalbased doses on but animal this experiments supposition and it is remains uncertain whether recreationalwould users suffer of from aminoindanes neurotoxicity. Johnson Marona-Lewicka models strongly indicate thatto the MDMA serotonergic is system, but neurotoxic,to neurotoxicity particularly in be humans fully remains resolved. 6-methylenedioxy-2-aminoindane (MDAI)methyl-2-aminoindane (MMAI). and Nichols be the 5-methoxy-6- case with 5-iodo-2-aminoindanefor (5-IAI) MDMA which in substituted rats. are trained to respond tosubstituting certain for drug MDMA, effects the andthe aminoindanes empathogenic behaviour. and are By entactogenic effects likely of serotonin to releasing drugs. In produce fact Monte selective in inducing the releaseMMAI of was neuronal unlikely serotonin; to alsoand have that that amphetamine the or drug’s LSD-liketo overall properties its behavioural serotonergic effects. profile would be related Pharmacology Although Solomons and Sam reporteddanes in 1973 that possessed the aminoin- properties, significant bronchodilating and analgesic 2011 John Wiley & Sons, Ltd. lly rigid analogue of amphetamine. Internet websites offering c [1] R.P. Archer, a Accepted: 24 May 2011 -iodo-2-aminoindane (5-IAI), oindane (MMAI), although some ∗ A.T. Kicman, a a -methyl-2-aminoindane (MDMAI), 5-iodo-2-aminoind N aminoindanes; legal highs; MDAI; MDMAI; 5-IAI; MMAI; serotonin. -alkylation. Internet websites offering synthetic com- N Figure 1 illustrates that 2-aminoindane is a conformationally -methyl-2-aminoindane (MDMAI), 5 (MMAI). The chemistry, pharmacology, andthese toxicological could aspects become of the this next new wave class of of ‘legal psychoactive highs’. substances Copyright are reviewed, as Keywords: and 5-methoxy-6-methyl-2-amin caution must alwaysticity be exercised of as theand to compounds the other chemical supplied.successors derivatives authen- It of of mephedrone isa and 2-aminoindane possible other new could cathinone that wavequences. become derivatives these, of as the ‘legal’ designer drugs with unknown conse- and some otherintroduced countries. in This 2010 controlassociated to measure with the deal was use of with urgently mephedrone.of a However, what precise cluster role details mephedrone ofunclear played as alleged there in have been fatalities these no systematic fatalities humanof or still animal the studies remains acute andhighs are chronic analogues effects of substances oflegal that this control, have drug. been presumably placed Manyexperiences. to under Such new give a legal group similar of(aminoindans). or compounds are new the psychotropic aminoindanes rigid analogue oftem. The amphetamine basic duesuch structure to can as be its substitutionfunctional altered closed groups, in in or a ring the theand number sys- addition also aromatic of of ways, a ringpounds methylenedioxy with as bridge, ‘research a chemicals’5,6-methylenedioxy-2-aminoindane variety (MDAI), have 5,6-methylenedioxy- recently of beenN advertising Historically, the terms ‘legal highs’blends and of ‘herbal highs’ psychoactive referredor plants to ingested or fungi toThese that induce terms, could dissociative however, bedescribe effects have smoked an and more extensive hallucinations. andsubstances recently that growing been have range widened become ofabuse; to popular entirely this as synthetic coincides recreationaland with drugs legislative of activity a as period governmentsAmerica try across to of address Europe the complex and intense legal status North ofRecently such media substances. popular interest legal(mephedrone) highs, and such related asnaphyrone cathinones 4-methylmethcathinone have such been as placed methylone under and legal control in the UK Introduction synthetic compounds as ‘research6-methylenedioxy- chemicals’ have recently been Due to its closed ring system, 2-aminoindane is a conformationa P.D. Sainsbury, (www.drugtestinganalysis.com) DOI 10.1002/dta.318 Aminoindanes – the next wave of ‘legal highs’? Review Received: 23 May 2011 R.A. Braithwaite . 2 et al NH Other H N [3,5,10] . described the P. Sainsbury et al 8. 10. C C hydrogenation. Both Nichols 3 3 F F via It should be noted that there is . have indicated that serotonin- 2 [11] et al H N NH [5,9] . successfully used palladium supported on -ethyl-5-trifluoromethyl-2-aminoindane ETAI), N et al The method utilises the intramolecular cyclisation . and Monte [9] [7] 7. 9. et al Fenfluramine (7) and ETAI ((8); norfenfluramine (9) and TAI (10). . showed that these indanes are capable of causing an . and Monte C C 3 The initial step for creating an aminoindane from a dihy- 3 F F carbon as the catalyst. Synthesis of aminoindanes Analogues of 2-aminoindanesusing have indanone, historically been indenethe prepared or acyl after chlorideknown intramolecular derivative as of cyclization 3-phenyl-2-propanoic dihydrocinnamic of procedure acid for acid. synthesising also Nichols aminoindanesin Scheme such 1. as MDAI shown Figure 2. a ‘cocktail’ withamphetamine, well-established or stimulants methamphetamine.associated However, such with this as anJohnson could cocaine, unexpected be toxicity. Studies reported by releasing agents generallyacting potentiate dopaminergic theof effects drugs of dopamine and indirectly in point both out neuro- the and involvement cardiotoxicity. aminoindanes that have been soldthe online indane as analogues legal of highsof the include fenfluramine, anorectic typeand drugs such that as of(TAI)(Figure that 2). norfenfluramine, Studies 5-trifluoromethyl-2-aminoindane et carried al out onindirect serotonergic rats effect. reported by Cozz some evidence thatloss long-term use (withdrawn of somecause fenfluramine years for deficiencies weight agoassociated in due with serotonin possible touseful signs population transporters cardiotoxicity) (ex-fenfluramine users) of for further may that investigation, neurotoxicitywhere and might the may confounding be be variableproblematic. of a multiple drug abuse is less of 3-(3,4-methylenedioxyphenyl)propionyl chloride (a) to formindanone an (b), followed by treatment with amyland nitrite HCl in methanol to yield anusing oxime palladium (c). produces A the catalytic 2-aminoindan hydrogenationis analogue isolated reaction (d), as which the HCl salt. drocinnamic acid requires conversionan acid of chloride using the a carboxylic chlorinatingpentachloride. reagent Intramolecular acid cyclisation such of as the to dihydrocinnamoyl phosphorus chloride produces an indanone. Treatmentan of alkyl the indanone nitrite with underketone. acidic The conditions final yields stagethe the of oxime hydroxyimino the to synthesis theet involves aminoindane al a reduction of . [3] 2 2 NH et al NH In the NH [9] -methyl-2-aminoindane N O O I The pharmacological action 4. 6. 2. [10] 2 2 2 NH NH However, extrapolation to likely human NH [4] By examining rat-brain monoamine levels, it [3,5,8] The structures of amphetamine (1) in comparison with O O O 1. 3. If aminoindanes such as MDAI and MMAI are to enjoy the MMAI, MDAI, and 5-IAI appear to affect the 5-HT system, but 5. Drug Testing Drug Analysis and of MDMA and MDAkey on these behind particular the neurotransmittersTherefore, extensive is the the purely historical serotonergic popularity actionunlikely of to of the produce these aminoindanes the is combination drugs. stimulation, of sought desired effects, after including by thebut drug this taking community could atunanticipated lead large effects. to the taking ofrelative much larger popularity doses, withsuch with drugs as users the cathinones, as it previous is legal possible highs they will be taken as has been shown that MMAI caused an acute(and reduction in its serotonin metabolite 5-HIAA) inbut the frontal no cortex change or in hippocampus, noradrenaline and an increase in dopamine. study by Nichols on 5-IAI,in only slight rodents neurotoxicity at was very observed toxicity high was doses only and foundthat that at already significant doses approaches the serotonergic higheranalogues lethal than in level 40 rodents. for mg/kg, many a amphetamine dose Thesemonoamineswerenodifferenttocontrolvalues1to2after weeks dosing and, unlikewas some no selective substituted degeneration of amphetamines, serotonergic axons. there Nichols (MDMAI) (4), 5-methoxy-6-methyl-2-aminoindane (MMAI) (5)2-aminoindane and (5-IAI) (6). 5-iodo- 5-IAI (Figure 1) areagents, highly they potent alsoany selective report serotonin long-term that releasing neurotoxicityadministered. these in analogues animal did not studies show at the levels Figure 1. 2-aminoindane (2) toaminoindane (MDAI) show (3), 5,6-methylenedioxy- their similarity; 5,6-methylenedioxy-2- also reported a similarfrontal lack cortex and of hippocampus brain neurotoxicity region, their foring results that no indicat- MDAI loss of in serotonin uptake sites the hadreflecting occurred, the rat presumably absence of serotonin terminal degeneration. acute toxicity following abuse of very high doses is not possible. have an absencereceptors. This of would action suggestnoradrenaline on levels stimulation in of dopamine the dopamineamphetamine brain and and/or plays analogue a noradrenaline critical neurotoxicity.shown role that It in MDA reported and has MDMAserotonin, inhibit previously dopamine, the and synaptosomal been noradrenaline, uptake andof of induce serotonin the from release synaptosomes.

480 481 Drug Testing Drug Analysis and OH 3 ONO 11 en.pdf [29 May 2010]. n of 1-(3-methoxy-4-methyl- H 5 Toxicological studies need to C 2 H+ / CH studies on cell cultures, as well NH [15,16] 20101144 O 16, 1330. 34, 1662. in vitro 1973, 1991, d b O O O O J. Med. Chem. and pharmacologicalphenyl)-2-aminopropane and examinatio 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamineJ. Med. Chem. (MDMA). Control of mephedroneOfficeCircular010/2009,London.Ava andilableat:http://www.opsi.gov. other cathinoneuk/si/si2010/em/uksiem derivatives. Home [2] E. Solomons, J. Sam. 2-aminoindans[3] of pharmacological M. P. interest. Johnson, S. P. Frescas, R. Oberlender, D. E. Nichols. Synthesis [1] The Home Office. A change to the Misuse of Drugs Act 1971: The rapid creation of analytical profiles on the researched References be undertaken in orderaminoindanes to may assess have the on potential potentialon damage users; that a this the better could beactivity understanding based of relationships, drugas structure–pharmacological animal studies usingevaluation. selected Further research compounds should for alsoof more investigate polypharmacy detailed the dangers with2-aminoindane novel analogues with dopamine compounds. releasing agents and/or Thereuptake combination inhibitors of hastoxicity the profile potential of toingestion, particularly these significantly in naive chemicals alter users. following the acute oraminoindanes, chronic using the majorand spectroscopic, chromatographic mass spectrometriccost-effective assistance techniques, in wouldenforcement drug agencies, provide identification as well for valuable asunexpected the relevant or more suspicious law rapid deaths. investigation What of will is clear continue is to that present legal significantscientists highs challenges and and politicians problems as for population a continue to sizable look proportion for new of ways the of intoxication. younger set of effects that createsexperience or if enhances it a is pleasurablewith to recreational mephedrone. reach If the the same aminoindanes,in dramatic taken ‘cocktails’, levels by of do themselves, use not or they seen give are unlikely users to the make highThis a significant they has impact are on already seeking, the4-methylthioamphetamine drug then been scene. being encountered a withcausing poor a a substitute number phenylethylamine; for ofrepeated MDMA, doses fatalities to in seek userspossibly increasing a whom the risk desired of most overdose effect, due likelythe to a the took initial perception slow that dose onset was of too action low. Pd/C have [13] Catalytic Reduction Intramolecular cyclisation Intramolecular Cl OH N O and also Elliott O [12] c a procedure for synthesising 5,6-methylenedioxy-2-aminoindane (MDAI). [9] Relying solely on existing drugs misuse O O O O et al [14] The Nichols Numerous legal highs are widely available on the Internet as Although this review suggests the aminoindanes may be set to Aminoindanes – the next wave of ‘legal highs’? suppliers attempt to replacerecently and banned emulate cathinone the analogues. popularitymade Many for of of the the these market drugsanalogues based are of on compounds research from firstAlexander animal synthesized Shulgin. studies, and or documented by discussed the ongoing challengescologists in presented the detection to and measurement analyticalsubstances. of For materials toxi- new obtained psychoactive in illicit drug seizures, structural characterization is largely reliantcomparison on of spectroscopy, data where can useful that also have be already made to beenreliance on analogous high characterized, resolution substances mass as spectrometry for wellysis. elemental anal- NMR, as infra-red an and increasing suitable, for Raman the spectroscopy, subsequent identification however, of suchical are drugs in matrices, not biolog- where thereto is the a domination specificity of matrix problem, effectsas primarily (even after due a extraction), concentration as well issuethan 1 (analyte mg/ml). concentrations The clinical areheavily and much reliant forensic on toxicologist less chromatography-mass is, spectrometry therefore, fication for identi- of new substances, givencross-reactivity current in limitations established concerning immunoassayso, there drug is screens. an inevitable Even delayto before mass these spectral substances libraries, are added as wellthe as the lack problems of associated with metabolites availability of of drugs, reference onceerence standards identified). standards (including for With major the respect1-aminoindane, aminoindanes, to 2-aminoindane it and the is MDAI ref- advantageousfor are that example, already from available, LGC Standardslaunched, (UK), MDMAI 5-IAI is is under tobeen current added be development, to imminently and their MMAI targetaside, has list tetralins of that materials are fornow production. structurally being As similar supplied an to (methylenedioxyaminotetraline; aminoindanes, MDAT)prepared are (6,7-methylenedioxy-N-methyl-2-aminotetralin). and Recently Wohlfarth and Weinman Analytical and other aspects Scheme 1. replace the cathinones as theforegoneconclusion. next Anynewdrug legal high, willhavetoproducearequired it is by no means a legislation may notnew be compounds enough and a to moreto intelligent control and the recreational pragmatic approach supply drugis of use these established needs more toevidence-based risk on be assessment of public urgently new substances health of sought, abuse. warnings which supported by . et al Report 24, 85. 59, 709. , Transform 2000, H] Monoamine 1998, 3 P. Sainsbury J. Anal. Toxicol. properties of 3,4-methylene- Lewicka, X. M. Huang, D. E. Nichols. 1999. , 249. 3 200,9. PIKHAL: A Chemical Love Story . Luxembourg: Office for Official Publications Pharmacol. Biochem. Behav. , 965. 2011, 2 1991, 1991. 2010, Bioanalysis Indan analogs of fenfluramine andneurotoxic potential. norfenfluramine have reduced Bioanalysis drugs. releasing anddioxymethamphetamine uptake and inhibition para-chloroamphetamineEur. J. analogs. Pharmacol. 4-methylthioamphetamine (4-MTA). Press: California, on the Risk Assessment of 4-MTAon in New the Synthetic Framework Drugs of the Jointof Action the European Communities: 1]MPJhsn ..oat,DENcos [ D.E.Nichols. P.F.Conarty, M.P.Johnson, [10] [11] N. V. Cozzi, S. Frescas, D. Marona- [12] A. Wohlfarth, W. Weinman. Bioanalysis of new designer drugs. [13] S. Elliott. Cat and mouse:[14] The A. Shulgin, analytical A. toxicology Shulgin. of designer [15] European Monitoring Centre For Drugs and Drug Addiction. [16] S. P. Elliott. Fatal poisoning with a new phenylethylamine: 106, J. Med. 2010, Pharmacol. 33, 703. 106, 787. 1990, 53, 99. Addiction 2011, . (2011): Strengthening the 1996, et al nt serotonergic neurotoxicity in d indan analogs of 3,4-(methy- J. Med. Chem. Addiction 38, 135. 1991, 36, 3700. Pharmacol. Biochem. Behav. 1993, 777. case against functionally significa H. G. Pope. Residual neurocognitiveusers features with of minimal long-term exposure ecstasy to other drug. human MDMA (ecstasy) users. Reinforcing effects ofderivatives. certain serotonin-releasing amphetamine Riggs. Nonneurotoxic tetralinlenedioxy)amphetamine an (MDA). a nonneurotoxic analogBiochem. Behav. of para-iodoamphetamine. and pharmacologicaltetralin examination analogs ofChem. of benzofuran, 3,4-(methylenedioxy)amphetamine. indan, and [7] M. Lyvers. Commentary on Halpern, [6] J. H. Halpern, A. R. Sherwood, J. I. Hudson, S. Gruber, D. Kozin, [8] D. Marona-Lewicka, G. S. Rhee,[9] D. J. E. E. Sprague, Nichols, W. K. Brewster, M. D. E. P. Nichols. Johnson, R. Oberlender, R. M. [4] D. E. Nichols, M. P. Johnson, R. Oberlender. 5-iodo-2-aminoindan, 5 A.P.Monte,D.Maronalewicka,N.V.Cozzi,D.E.Nichols.Synthesis [5] Drug Testing Drug Analysis and

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