Drug info - 2 aminoindan ?Amphetamine analogue?

[argovistov]

Please post info about 2-AI here.

Please post information about:

• Names / synonyms
• Molecule
• Dose
• Duration
• Legal status
• Reported incidents/fatalities
• Since when has this research chemical been available
• Stability
• if this compound detectable in drug tests & for how long
• Reaction to Marquis or other tests.
• Tolerance & Cross-tolerance
• Appearance (visual, smell, taste, crystal/powder)
• Forms commonly available & routes used with each.
• Common Effects: Main (During & after), Side (long & short term)
• Any known drug & food interactions

Experiences with 2-AI should be discussed here:
These documents about 2-AI are in the file archive
2-AI pics
Research Chemicals Index - Phenethylamines
Research Chemicals Index - Tryptamines
__________________________________________________ ________________________________________________
Any thoughts of MBDB and 2-Amino Indan? Not easy to find tripreports for them. Both still legal here in europe.

[Alfa]

The early warning system of the INCB (EU) has made a risk assesment of MBDB. I do not know what they did with it. The risk assesment is nowhere to be found on the net.


2-aminoindan is AKA MMAI and has several varieties.I found this on the net: "There is a research chemical called 2-amino indan, which is the
amphetamine molecule, with the free end of the side chain warpped back
around and re-attached to the benzene ring. It is an excellent
stimulant, much like amphetamine itself. Dr. Nichols (if I remember
his name correctly) has done various experiments with derivatives of
2-amino indan, including the 5-iodo, methylenedioxy, and
trifluoromethyl derivatives and found them to be of reduced toxicity
but not reduced effects. I believe the plain 2-amino indan was
mentioned in PIHKAL also, which is what motivated me to try it.
I had occasion to try 2-amino indan about a year ago, and was very
pleased with it, as were others in the industrial workplace
environment.
If you do try it, do not go overboard, as it is very strong. "


Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA). (1990 Nichols)
Four cyclic analogues of the psychoactive phenethylamine derivative 3,4-(methylenedioxy)amphetamine were studied. These congeners, 5,6- and 4,5-(methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and 5,6-(methylenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Two groups of rats were trained to discriminate either LSD tartrate (0.08 mg/kg) from saline, or (+/-)-MDMA.HCl (1.75 mg/kg) from saline. In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine 1-(2,5-dimethoxy-4- methylphenyl)-2-aminopropane (DOM) were also evaluated. None of the methylenedioxy compounds substituted in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained rats. Compounds 4a and 4b did not substitute in MDMA-trained rats. 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. In view of the now well-established serotonin neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue 1, 3a and 3b were evaluated and compared to 1 for similar toxic effects following a single acute dose of 40 mg/kg sc. Sacrifice at 1 week showed that neither 3a nor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA levels nor were the number of binding sites (Bmax) depressed for [3H]paroxetine. By contrast, and in agreement with other reports, 1 significantly depressed all three indices of neurotoxicity. These results indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but that they lack similar serotonin neurotoxicity.

[Alfa]

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. (1999 Nichols)
The effects of two selective 5-HT-releasing agents, 4-methylthioamphetamine (MTA) and 5-methoxy-6-methyl-2-aminoindan (MMAI), on the extracellular 5-HT concentration in the dorsal hippocampus was determined by microdialysis in anesthetized rats. After i.p. administration of 1 or 5 mg/kg of either compound, a rapid and significant increase of 5-HT basal release was observed. MTA (5 mg/kg) induced a maximal increase of about 2000% over the basal value 40 min after injection, which declined slowly, whereas MMAI (5 mg/kg) induced a maximal response of about 1350% which showed a rapid decline. monoamine oxidase-A inhibitory properties of MTA, and MMAI's lack of similar properties might account for the difference between the two compounds. In agreement with previous information, a much lower increase in hippocampal 5-HT was observed in response to systemic fluoxetine. This difference in the magnitude of the response after MTA or MMAI and fluoxetine indicates that different mechanisms of action are operating. Based on evidence showing that an acute enhancement of 5-HT neurotransmission might result in the rapid appearance of therapeutic effects of serotonergic antidepressants, we suggest that MTA and MMAI might serve as leads for a novel family of compounds with a short onset of action useful for treating depression.

[Alfa]

Studies on the mechanism of p-chloroamphetamine neurotoxicity. (1996)
Studies were conducted to investigate the sensitivity of p-chloroamphetamine (PCA)-induced neurochemical changes to various pharmacological manipulations known to block the neurochemical effects of 3,4-methylenedioxymethamphetamine (MDMA). The monoamine oxidase-B (MAO-B) inhibitor L-deprenyl (2 mg/kg) given 4 hr before a nonneurotoxic dose of PCA (2 mg/kg) was shown not to alter the amount of [3H]paroxetine bound to serotonin (5-HT) uptake sites 7 days after treatment. L-Deprenyl 4 hr before a neurotoxic dose of PCA (10 mg/kg) did not change the acute hyperthermia. Further, neither L-deprenyl nor another selective MAO-B inhibitor, MDL-72,974 (1.25 mg/kg), given 30 min before or daily for 4 days before a single dose of PCA attenuated or potentiated the decrease in the number of [3H]paroxetine binding sites measured 7 days after PCA treatment. The combination of the MAO-A inhibitor clorgyline (2.5 mg/kg) or a nonspecific dose of L-deprenyl (10 mg/kg) with the selective 5-HT releasing agent 5,6-methylenedioxy-2-aminoindan did not lead to changes in the levels of 5-HT, 5-hydroxyindoleacetic acid or dopamine 7 days after treatment. Finally, the 5-HT2A receptor antagonist MDL-11,939 (5 mg/kg) did not protect against the neurotoxicity of PCA. By comparing the present work with previous studies of MDMA, these results can be interpreted to suggest that the mechanism of the neurotoxicity induced by PCA is not identical to that induced by MDMA. The relationship of these results to the neurotoxicity induced by MDMA is also discussed.

[Alfa]

Nichols 1998. N-Ethyl-5-trifluoromethyl-2-aminoindan (ETAI) and 5-trifluoromethyl-2-aminoindan (TAI) were synthesized to examine the effects of side-chain cyclization on the pharmacology of the anorectic drugs fenfluramine (FEN) and norfenfluramine (norFEN), respectively. ETAI and TAI inhibited synaptosomal accumulation of 5-HT but were less effective at inhibiting catecholamine uptake than FEN or norFEN, respectively. In vivo, ETAI and TAI were less neurotoxic than FEN or norFEN; decreases in the number of [3H]paroxetine-labeled 5-HT uptake sites were 50% less than the decreases produced by FEN or norFEN. Rats treated with ETAI. TAI, FEN, and norFEN lost 10-15% of their pretreatment body weight over a 4-day period, while saline-treated control animals gained 8%. In two-lever drug discrimination (DD) assays in rats, TAI fully substituted for the 5-HT releaser/uptake inhibitor, (+)-MBDB [(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane]. ETAI produced only partial substitution in this test. Neither TAI nor ETAI mimicked (+)-amphetamine in the DD assay. These studies demonstrate that incorporation of the side-chain of phenylisopropylamines into the five-membered ring of a 2-aminoindan changes both the molecular pharmacology and the neurotoxic profile of FEN and norFEN, but does not diminish the drugs' ability to reduce body weight.

[Alfa]

1996 Nichols. The drugs 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAI) and p-methylthioamphetamine (MTA) have been suggested to be 5-HT releasers. The present study characterized MBDB, MMAI and MTA by using their effects on the secretion of the hormones adrenal corticotrophin (ACTH), corticosterone, prolactin, oxytocin and renin. The time course of the effect of MBDB, MMAI and MTA (5 mg/kg, i.p.) showed that the peak effect on plasma ACTH occurred 10 min after the injection, whereas the prolactin response did not reach a maximum until 30 min after injection. MBDB increased plasma renin concentration within 10 min, whereas the effect of MTA was significant only at 30 min after injection. All three 5-HT releasers decreased HR (within 5 min) and blood pressure (at 15 min after injection). MBDB, MMAI and MTA increased plasma ACTH, corticosterone, prolactin and renin levels in a dose-dependent manner, whereas no changes were observed in plasma vasopressin concentrations. MTA and MMAI, but not MBDB, significantly increased plasma oxytocin concentrations in a dose-dependent manner. Pretreatment of rats with fluoxetine blocked the ACTH response to MBDB and MMAI, but not to MTA. The prolactin response to all three 5-HT releasers was blocked by fluoxetine. The oxytocin response to MTA and MMAI was inhibited by fluoxetine. The renin responses to all three 5-HT releasers were not significantly inhibited by fluoxetine. The results suggest that MBDB, MMAI and MTA can increase the secretion of several hormones, at least in part, through stimulation of serotonergic neurotransmission. However, these three 5-HT releasers seem to have effects on other (and as yet uncharacterized) mechanisms that can stimulate the secretion of some hormones.

[Alfa]

1996 Nichols. The present study was designed to characterize further the rewarding and aversive properties of 3,4-methylenedioxymethamphetamine (MDMA), the alpha-ethyl homologue of MDMA (MBDB), fenfluramine, and the selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan (MMAI) using the conditioned place preference paradigm (CPP). Extracellular dopamine (DA) and its metabolite DOPAC were also measured in the nucleus accumbens after systemic drug administration, using in vivo microdialysis in freely moving rats. MDMA produced a positive dose-dependent effect in the CPP test, which was maximal at doses of 5 and 10 mg/kg. MBDB also induced a positive CPP, with a maximum effect at 10 mg/kg. The conditioning effect of MBDB was more than 2.5-fold weaker compared with MDMA. Fenfluramine evoked place aversion at doses of 4, 6, and 10 mg/kg. This effect of fenfluramine was independent of dose. MMAI at doses of 1.25, 2.5, and 5 mg/kg produced no significant effect on place conditioning. At doses of 10 and 20 mg/kg, MMAI produced an effect similar to fenfluramine: Place aversion was independent of dose. In the microdialysis experiments, MDMA significantly elevated extracellular DA and induced a decrease of DOPAC in the nucleus accumbens. Thus, activation of dopaminergic systems may be responsible for the rewarding properties of MDMA-like drugs. In contrast to the effects seen with MDMA, no difference in extracellular DA or DOPAC was seen after injection of MBDB, fenfluramine, or MMAI, even though MBDB weakly induced a place preference. The mechanism responsible for the development of place aversion by fenfluramine or MMAI is unknown at this time and requires further study.

[Alfa]

Steric effects of substituents on phenethylamine hallucinogens. 3,4-(Methylenedioxy)amphetamine analogues alkylated on the dioxole ring. (Nichols 1979)
The compounds 1-(2-methyl-1,3-benzodioxol-5-yl)-2-aminopropane and 1-(2,2-dimethyl-1,3-benzodioxol-5-yl)-2-aminopropane were synthesized and evaluated for pharmacologic effects in mice. These can be viewed as analogues of the known psychotomimetic agent 3,4-(methylenedioxy)amphetamine (MDA). Their hydrochloride salts were compared with MDA for their ability to increase spontaneous motor activity and to elicit behavioral effects. The former compounds was MDA-like in action, while the latter was not. The results suggest that one face of the molecule must be free of steric bulk to possess activity.


This indanylamphetamine, (also called IAP, 1-(5-Indanyl)-2-aminopropane or 5-(2-aminopropyl)indane) is an analog of MDA, but with both oxygens in the methylenedioxy bridge replaced by methylene (CH2) units. It has been shown to not be a serotonergic neurotoxin, and is active at 0.2 mg/kg in Nichols' lab rat tests, compared to 0.8 mg/kg for MBDB. However, the lab rat results show that the effects should be somewhere inbetween MDA and MBDB, as it doesn't fully substitute for the purely serotonergic compound MMA (3-Methoxy-4-Methyl- Amphetamine), but does share some of the dopaminergic effects of MDA. Further animal tests showed that IAP does not substitute for amphetamine, so the compound is not a particular stimulant either. IAP is also one of the most active serotonin-releasing agents known so far, together with the 4-iodoamphetamine and 4-methylthioamphetamine (4-MTA). However, 4-iodoamphetamine is a serotonergic neurotoxin, and 4-methylthioamphetamine has also shown signs of toxicity, as it also exhibit MAOI properties. This together with is serotonin-releasing properties, makes it prone to give a serotonin syndrome in people taking it, and several 4-MTA related deaths has been reported. The same cannot be ruled out for IAP, so caution is advised in any human testing of this compound. The animal test results suggest that the active dose is somewhere between 20-40mg. In October 1998, there were news reports that the compound had been seized together with other ecstasy-like compounds in South Australia (possibly Adelaide), confirming that it has been manufactured in clandestine laboratories there.


The indane is formylated here through Friedel-Crafts alkylation with dichloromethyl methyl ether using Tin(IV)Chloride as the Lewis acid. There is no other regioselective formylation of indane available in the literature as far as I can tell. Vilsmeier formylation gives a lot of tar, and the products are both the 4- and 5-carboxaldehyde. The intermediate product from the alkylation hydrolyzes to the aldehyde in water. To purify the aldehyde, it is stirred with activated carbon (such as powdered Norite), and then filtered through some silica gel and Celite. The crude aldehyde is pure enough for subsequent reactions described here, but can be purified by making its bisulfite adduct, washing this, and then decompose it by the addition of concentrated potassium carbonate solution, followed by extraction into dichloromethane and evaporating.


Preparing the nitropropene is pretty straight-forward, just a reflux with ammonium acetate and nitroethane, but the purification is more of a hassle, since it is an oil at normal temperatures, and it cannot be distilled. The best method seems to be to wash the reaction mixture with water until all the inorganics and nitroethane has been removed, dilute with methylene chloride and dry the solution over MgSO4, evaporate the solvent and running the nitroalkene through a short column packed with silica gel.


The final reduction of the nitropropene and the subsequent isolation of the final indanylamphetamine is pretty straightforward, and the final product can be recrystallized from isopropanol/ether to improve the melting point. The overall yield of IAP from indane is 54% of theory, which is pretty good.


Indane-5-carboxaldehyde: 10g (84.6 mmol) of indane was dissolved in 100ml dichloromethane and cooled to 0°C on an ice bath. With vigorous stirring, 15ml (127 mmol) SnCl4 was added all at once via syringe, folllowed by the dropwise addition of 9.72g (7.65ml, 84.6 mmol) dichloromethyl methyl ether over a 10-minute period. After 30 minutes, the ice-bath was removed and the reaction was quenched by the addition of 125ml ice-water. The aqueous layer was discarded, and the organic phase washed with 3x100ml water, 3M HCl (3x50ml) and 2x50ml brine. The organic solution was stirred with activated carbon and filtered through a thin pad of silica gel on celite. After removal of the solvent, the residue consisted of 12.2g (98%) of a yellow oil pure enough for the next step.


5-indanyl-2-nitropropene: Indane-5-carboxaldehyde (4.0g, 15.9 mmol) was heated at reflux with 30 ml of nitroethane and 1.22g (15.9 mmol) of ammonium acetate for 4h to yield 2.43g (76%) of the nitropropene as a yellow oil which could be crystallized with difficulty from methanol after chromatography (CH2Cl2), mp 33-34°C.


Indanylamphetamine: 2.9g (14.3 mmol) of 5-indanyl-2-nitropropene in 100ml dry THF was added slowly to a stirred suspension of 1.5g (35.6 mmol) LAH in 150ml dry THF and the reaction was stirred for 5h at room temperature. Excess LAH was destroyed with the addition of 10ml H2O, the mixture filtered through celite, the filter cake rinsed well with ether and the solvent evaporated on a water bath. The residue was taken up in 100ml ether, extracted with 5x50 ml 3M HCl. The extracts was basified with 25% NaOH and extracted with 3x50ml DCM. The solution was dried over MgSO4, filtered and the solvent evaporated. The residue was taken up in 20 ml ether and gassed with dry HCl gas. Yield after filtering and drying, 2.18g (72%), mp 218-219°C.

[Alfa]

Between al the synthesis information, the information on the substances given seem very interesting. Needless to say that these research papers are old, dating from the time when 4-MTA was not considered deadly. Does anybody have more info on these very interesting synths?

[Alfa]

Synthesis and Pharmacological Evaluation of Ring-Methylated Derivatives of
3,4-(Methylenedioxy)amphetamine (MDA)
Matthew A. Parker, Danuta Marona-Lewicka, Deborah Kurrasch, Alexander T. Shulgin,‡ and David E. Nichols*
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences,
Purdue University, West Lafayette, Indiana 47907
Received September 5, 1997
The three isomeric ring-methylated derivatives of the well-known hallucinogen and entactogen
MDA (1a) were synthesized and evaluated for pharmacological activity as monoamine-releasing
agents and as serotonin agonists. The 2-methyl derivative 2a and the 5-methyl derivative 2b
were found to be more potent and more selective than the parent compound in inhibiting [3H]-
serotonin accumulation in rat brain synaptosomal preparations. Their activity in vivo was
confirmed in rats trained to discriminate serotonin-releasing agents and hallucinogens from
saline. The results indicate that compounds 2a,b are among the most potent 5-HT-releasing
compounds known and show promise as lead compounds in the search for antidepressant drugs
that release serotonin rather than inhibit its uptake.
Introduction
MDA (3,4-(methylenedioxy)amphetamine, 1a) is a
ring-substituted phenethylamine derivative first synthesized
in 1912 during early studies of phenylalkylamines.
1 It is of considerable interest in that it shares
structural and pharmacological properties with both
classical phenethylamine hallucinogens, the prototype
of which is mescaline,2 and entactogens, a class of
potentially therapeutically useful compounds including
1b (MDMA)3 and 1c (MBDB)4 that facilitate communication
and introspective states. These compounds
exert their psychological effects by modulating monoamine
neurotransmitter systems in the central nervous
system (CNS). The hallucinogens are, in general, direct
serotonin (5-HT) agonists acting primarily at 5-HT2
receptor subtypes,5 whereas the entactogens exert their
effects indirectly by inducing the presynaptic release of
5-HT, dopamine (DA), and norepinephrine (NE). As
MDA lies at the intersection of these two classes, it
provides an excellent starting point for examining
effects of variation in structure on the action of these
compounds.
We have for the past several years been particularly
interested in the activity of ring-substituted phenethylamines
as selective serotonin-releasing agents.6,7 We
wished to explore this area further, especially in light
of the recent demonstration in our laboratories that
certain compounds which act as selective 5-HT releasers
possess antidepressant properties in a rat model of
depression.8 Thus, our primary rationale for the synthesis
of the current compounds was to examine the
effects of ring methylation on their potency and selectivity
as releasers of 5-HT versus DA and NE.
Four ring-methoxylated analogues of MDA were
previously examined as 5-HT- and DA-releasing agents,
but none surpassed the parent compound in potency,
nor did any exhibit significant selectivity for neurotransmitter
release.9 However, as these compounds
have several relatively polar ether substituents on the
aryl ring, they are too hydrophilic to have optimal CNS
activity.10 It seemed, then, that ring methylation to give
2a-c might lead to more active compounds by increasing
the overall lipophilicity relative to that of the parent
compound. It also seemed likely that selectivity might
be increased, given our previous general observation
that the structural requirements for activity are more
stringent for the dopamine uptake carrier than for the
serotonin carrier.7
In addition, we hoped to reinforce earlier evidence11
that suggested the active conformation of the aminoethyl
side chain in this class of molecules. In that study,
we found that the 2-aminoindan derivative 3, as well
as the corresponding 2-aminotetralin analogue, substitutes
for MDMA in rats trained to discriminate MDMA
from saline, whereas 4 and its tetralin analogue lack
activity. Later it was reported12 that 2,N-dimethyl-4,5-
(methylenedioxy)amphetamine (6-methyl-MDMA), the
N-methyl derivative of 2c, lacks entactogenic activity
* Address correspondence to: Dr. David E. Nichols. Phone: (765)
494-1461. Fax: (765) 494-1414. E-mail: drdave@pharmacy.purdue.edu.
‡ Present address: 1483 Shulgin Rd, Lafayette, CA 94549.
1001 J. Med. Chem. 1998, 41, 1001-1005
S0022-2623(97)00592-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/24/1998
in humans. We conjecture that this compound lacks
activity because the methyl group on the ring, through
steric repulsion, forces the side chain into an unfavorable
orientation like that in 4. The 2-methyl compound
2a, on the other hand, might be expected to retain
activity because the methyl group would direct its side
chain into a conformation similar to that found in 3.
We therefore describe here the synthesis of the three
isomeric ring-monomethylated derivatives of MDA, an
evaluation of their hallucinogen- and entactogen-like
behavioral effects in the rat, and the determination of
their potency in inhibiting the accumulation of tritiated
5-HT, DA, and NE into rat whole brain synaptosomal
preparations.
Chemistry
The synthesis of the target compounds was straightforward
starting from the appropriate substituted benzaldehydes.
Two of the three required aldehydes were
synthesized as described in the literature,13,14 and the
remaining aldehyde 5b (5-methylpiperonal) was obtained
by methylenating 4,5-dihydroxy-3-methylbenzaldehyde,
15 available in three steps from vanillin. The
aldehydes were converted into the corresponding phenylisopropylamines
by condensation with nitroethane
followed by reduction with lithium aluminum hydride
(Scheme 1), as described previously.16
Pharmacology
Compounds 2a-c were evaluated in the two-lever
drug discrimination assay in five groups of rats, each
of which was trained to discriminate the effects of ip
injections of saline from those of one of the following
drugs: (+)-amphetamine, (+)-MBDB, MMAI, LSD, and
DOI; the methods employed have been described previously.
16,17 For those compounds that completely substituted
for a training drug, potencies were calculated
as ED50 values with 95% confidence intervals.
In addition, the compounds were tested for their
ability to inhibit the accumulation of tritiated 5-HT, DA,
and NE into rat whole brain synaptosomes as also
described previously,6 and the data were used to calculate
IC50 values.
Results and Discussion
Results of the [3H]monoamine uptake inhibition studies
in rats are shown in Table 1. Most apparent from
the data is the fact that all three of the compounds are
almost completely inert at the dopamine uptake carrier,
being more than 10 times less potent than MDA in
inhibiting uptake of [3H]DA. They would therefore be
expected to lack the serotonin neurotoxicity associated
with the parent compound.18 Compound 2c shows
reduced activity at the 5-HT carrier as well, being only
about one-half as potent as the parent compound.
Compounds 2a,b, however, are quite potent at the
serotonin carrier, being 4-5 times more active than
MDA. All three compounds show modest activity in
inhibiting [3H]NE accumulation, with 2b being the most
potent.
The drug discrimination data for 2a-c are presented
in Table 2. As would be expected from an examination
of the uptake inhibition data, none of the compounds
substituted for the catecholamine releaser (+)-amphetamine.
The data from uptake inhibition are also borne
out in the behavioral data from rats trained using the
selective serotonin releasers (+)-MBDB and MMAI.
Compounds 2a,b substituted completely for both (+)-
MBDB and MMAI and were slightly more potent than
MDA in the (+)-MBDB-trained rats, whereas 2c exhibited
only partial substitution in (+)-MBDB-trained rats
and substituted in MMAI rats only at a relatively high
dose.
From Table 2 it can also be seen that 2a,b substitute
for the hallucinogenic 5-HT2A agonist DOI at doses
comparable to those at which they substitute for the
serotonin releasers (+)-MBDB and MMAI. Compound
2a also substitutes in LSD-trained rats, albeit at more
than twice the dose required in DOI-trained rats.
Compound 2c is once again only marginally active,
showing partial substitution at high doses in DOI- and
LSD-trained rats. Thus, 2a,b, but not 2c, retain the
hallucinogen-like behavioral effects of the parent compound
presumed to be mediated by the 5-HT2A receptor.
19
In summary, both the in vitro and in vivo data point
to 2a,b as serotonin-releasing agents more potent than
MDA, with 2a appearing to be slightly more potent than
2b in most of the assays. These data indeed support
our conjecture that in 2a, as well as 2b, the amine side
chain can assume a favorable conformation for interacting
with the serotonin carrier, whereas in 2c the side
chain is forced into an unfavorable position. Further
support for this idea was provided by a conformational
analysis employing semiempirical AM1 potential functions,
which indicated that conformations where the side
chain was directed toward the aryl methyl group in
either 2a or 2c were about 8 kcal/mol above the
minimum-energy conformation and about 6 kcal/mol
less stable than conformations where the side chain was
directed toward an aryl hydrogen atom.
Compounds 2a,b are particularly interesting in that
they are more potent as serotonin-releasing agents than
Scheme 1a
a (a) EtNO2, NH4OAc, reflux; (b) LiAlH4, THF.
1002 Journal of Medicinal Chemistry, 1998, Vol. 41, No. 6 Notes
most other compounds previously tested in these laboratories.
6,7,16 The only compounds that have shown
higher activity than 2a,b are p-iodoamphetamine (PIA),20
p-(methylthio)amphetamine (MTA),21 and 1-(5-indanyl)-
2-aminopropane (IAP).16 As can be seen in Table 1,
although PIA, MTA, and IAP are slightly more potent
than 2a,b, the latter two compounds greatly surpass
them in selectivity for 5-HT versus DA release, exhibiting
a preference of more than 100-fold for the 5-HT
carrier versus the DA carrier, while still retaining a
moderate selectivity versus the NE carrier.
Indeed, the present pharmacological data point to
2a,b as promising lead structures for therapeutically
useful agents in the treatment of depression. However,
the hallucinogen-like effects of these compounds would
need to be eliminated before this clinical application
could be considered. Several strategies to accomplish
this goal are currently underway.
Experimental Section
Chemistry. Melting points were taken on a Mel-Temp
apparatus and are uncorrected. 1H NMR spectra were recorded
using a 500-MHz Varian VXR-500S spectrometer.
Chemical shifts are reported in ‰ values ppm relative to
tetramethylsilane as an internal reference (0.03%, v/v). Elemental
analyses were performed by the Purdue University
Microanalysis Laboratory and are within 0.4% of the calculated
values. Most reactions were carried out under an inert
atmosphere of dry argon or nitrogen.
4-Methyl-1,3-benzodioxole-6-carboxaldehyde (5b). To
a mechanically stirred suspension of 4,5-dihydroxy-3-methylbenzaldehyde15
(12.84 g, 84.5 mmol) and cesium carbonate
(41.28 g, 126.7 mmol) in anhydrous DMF (200 mL) was added
BrCH2Cl (8.23 mL ) 16.39 g, 126.7 mmol), and the resulting
mixture was heated to 110 °C for 2 h. The reaction was then
cooled to room temperature and filtered through a pad of Celite
with EtOAc washing. The filtrate was concentrated almost
to dryness, diluted with H2O, and extracted three times with
EtOAc. The extracts were washed with H2O and brine, dried
with MgSO4, filtered, and evaporated, yielding 13.54 g (98%)
of product as a tan solid of sufficient purity to be carried on to
the condensation step. An analytical sample of 1.27 g gave
after bulb-to-bulb distillation (120 °C, 0.25 Torr) 1.05 g of a
white solid: mp 45-46 °C; 1H NMR (CDCl3) ‰ 2.29 (s, 3, CH3),
6.07 (s, 2, OCH2O), 7.19 (s, 1, ArH), 7.25 (s, 1, ArH), 9.78 (s, 1,
CHO). Anal. (C9H8O3) C, H.
4-Methyl-5-(2-nitro-1-propenyl)-1,3-benzodioxole (6a).
To a solution of 0.527 g of 2-methylpiperonal13 in 5 mL of
nitroethane was added 60 mg of ammonium acetate. The
mixture was stirred and heated at 85 °C for 22 h. The reaction
mixture was cooled, diluted with Et2O, washed twice with H2O,
dried with MgSO4, and filtered. The Et2O and excess nitroethane
were evaporated, and the yellow crystalline product
(0.69 g, 97%) was dried overnight under vacuum. An analytical
sample was recrystallized from MeOH: mp 91-92 °C; 1H
Table 1. IC50 for monoamine Uptake Inhibition in Rat Synaptosomesa
IC50 (nM) selectivity
compd [3H]-5-HT [3H]DA [3H]NE 5-HT/DA 5-HT/NE
1a (MDA)b 478 ( 40 890 ( 100 266 ( 28 2 <1
2a 93 ( 11 12000 ( 1260 1937 ( 329 129 21
2b 107 ( 12 11600 ( 970 1494 ( 411 108 14
2c 783 ( 68 28300 ( 7200 4602 ( 1390 36 6
PIAc 82 ( 8 589 ( 52 993 ( 86 7 12
MTAd 74 ( 10 3073 ( 407 2375 ( 121 42 32
IAPe 82 ( 6 1847 ( 213 849 ( 82 23 10
a The ability of the test compounds to inhibit accumulation of monoamines was examined in crude synaptosomes. The data from three
or four experiments were combined, and the IC50 values ( SEM (nM) were calculated by curve fitting followed by appropriate statistics
(see Experimental Section). b Values from Johnson et al.6 included for comparison. c p-Iodoamphetamine; values from Nichols et al.19
included for comparison. d p-(Methylthio)amphetamine; values from Huang et al.20 included for comparison. e 1-(5-Indanyl)-2-aminopropane;
values from Monte et al.16 included for comparison.
Table 2. Results of the Drug Discrimination Studies in Rats
training drug test drug ED50 (Ìmol/kg) 95% CIa (Ìmol/kg) nb
(+)-amphetamine (+)-amphetamine 1.06 0.65-1.73
1a (MDA) NSc 8-13
2a NSc 9-10
2b NSc 9
2c NSc 9-10
(+)-MBDB (+)-MBDB 3.25 2.10-5.03
1a (MDA) 2.07 1.31-3.26 9-12
2a 1.83 1.01-3.30 9-10
2b 2.00 1.23-3.25 9-11
2c PS (17.4, 78%)d 8-11
MMAI MMAI 1.83 1.15-2.91
2a 1.71 0.88-3.32 8-9
2b 1.53 1.15-2.05 8-10
2c 7.65 4.50-12.96 8-10
LSD LSD 0.04 0.02-0.06
2a 4.10 2.82-5.98 11-18
2b PS (8.72, 75%)d 10-15
2c PS (17.4, 60%)d 10-16
DOI DOI 0.30 0.20-0.47
2a 1.70 1.10-2.63 8-9
2b 2.11 1.06-4.20 8
2c PS (8.72, 63%)d 7-8
a Range of 95% confidence interval for ED50. b Number of animals tested at each dose. c NS, no substitution. d PS, partial substitution;
with the dose at which highest substitution occurred followed by the percentage of rats selecting the drug lever at that dose given in
parentheses.
Notes Journal of Medicinal Chemistry, 1998, Vol. 41, No. 6 1003
NMR (CDCl3) ‰ 2.22 (s, 3, vinylic CH3), 2.35 (s, 3, aryl CH3),
6.02 (s, 2, OCH2O), 6.73 (d, 1, ArH, J ) 8.05 Hz), 6.80 (d, 1,
ArH, J ) 8.05 Hz), 8.11 (s, 1, vinylic H). Anal. (C11H11NO4)
C, H, N.
4-Methyl-6-(2-nitro-1-propenyl)-1,3-benzodioxole (6b).
A mixture of 11.0 g (67.1 mmol) of aldehyde 5b, 40 mL of
nitroethane, 10.9 g (134 mmol) of dimethylamine hydrochloride,
0.58 g (10 mmol) of potassium fluoride, and 40 mL of
toluene was placed in a flask equipped with a Dean-Stark
trap and heated at reflux under N2 for 24 h. Solvents were
evaporated, and the residue was partitioned between Et2O and
H2O. The Et2O fraction was dried with MgSO4 and evaporated,
yielding 14.12 g (95%) of product as an orange-yellow
solid. An analytical sample was recrystallized from MeOH to
give pale-orange crystals: mp 97-98 °C; 1H NMR (CDCl3) ‰
2.26 (s, 3, vinylic CH3), 2.46 (s, 3, aryl CH3), 6.03 (s, 2, OCH2O),
6.80 (s, 1, ArH), 6.82 (s, 1, ArH), 8.00 (s, 1, vinylic H). Anal.
(C11H11NO4) C, H, N.
General Procedure for the Reduction of the Nitropropenes
6a-c to the Aminopropanes 2a-c. A solution
of 10 mmol of the appropriate nitropropene in 20 mL of THF
was added dropwise to a suspension of 70 mmol of LiAlH4 in
35 mL of THF while stirring under N2. The reaction mixture
was stirred and heated under reflux for the specified time and
cooled to room temperature, and the reaction was quenched
carefully by the sequential addition of 2 mL of 2-propanol, 2
mL of 15% aqueous NaOH, and 7 mL of H2O. The precipitate
was removed by filtration, and the resulting solution was
evaporated. The residue was suspended in H2O, acidified with
concentrated HCl, and washed three times with Et2O. The
resulting acidic solution was then made basic with aqueous
NaOH and extracted three times with Et2O. The Et2O solution
was evaporated, and the resulting oil was purified by bulbto-
bulb distillation. The distilled oil was dissolved in 10 mL
of 2-propanol, neutralized with ethanolic HCl, and diluted with
Et2O to yield the hydrochloride salt of the aminopropane.
1-(4-Methyl-1,3-benzodioxol-5-yl)-2-aminopropane Hydrochloride
(2a). This compound was obtained from 6a in
71% yield as fine white crystals: mp 214-215 °C; 1H NMR
(D2O) ‰ 1.13 (d, 3, CHCH3, J ) 7 Hz), 2.02 (s, 3, ArCH3), 2.73
(m, 2, ArCH2), 3.37 (sextet, 1, CH, J ) 7 Hz), 5.79 (p, 2,
OCH2O, J ) 1 Hz), 6.58 (s, 2, overlapping ArH). Anal. (C11H16-
ClNO2) C, H, N.
1-(4-Methyl-1,3-benzodioxol-6-yl)-2-aminopropane Hydrochloride
(2b). This compound was obtained from 6b in
65% yield as white crystals: mp 222-223 °C; 1H NMR (D2O)
‰ 1.11 (d, 3, CHCH3, J ) 7 Hz), 2.03 (s, 3, ArCH3), 2.65 (m, 2,
ArCH2), 3.38 (sextet, 1, CH, J ) 7 Hz), 5.79 (s, 2, OCH2O),
6.48 (s, 1, ArH), 6.51 (s, 1, ArH). Anal. (C11H16ClNO2) C, H,
N.
1-(5-Methyl-1,3-benzodioxol-6-yl)-2-aminopropane Hydrochloride
(2c). This compound was obtained in 74% yield
from 6c.14 The salt precipitated from 2-propanol/ether solution
as a clear oil which crystallized overnight as white crystals:
mp 157-158 °C; 1H NMR (D2O) ‰ 1.13 (d, 3, CHCH3, J ) 7
Hz), 2.07 (s, 3, ArCH3), 2.70 (m, 2, ArCH2), 3.39 (sextet, 1, CH,
J ) 7 Hz), 5.76 (tt, 2, OCH2O, J ) 1, 3 Hz), 6.59 (s, 1, ArH),
6.64 (s, 1, ArH). Anal. (C11H16ClNO2) C, H, N.
Pharmacology Methods. Animals. Male Sprague-
Dawley rats (Harlan, Indianapolis, IN) weighing 175-200 g
were used. Animals were group housed (for in vitro experiments)
or individually caged (for drug discrimination experiments)
in a temperature-controlled room with a 12-h day/night
lighting schedule. Animals that were used for in vitro experiments
were supplied with food (Lab Blox, Purina) and water
ad libitum.
Drug Discrimination. The procedures for the drug discrimination
assays were exactly as described previously.16,17
Training drugs were (+)-amphetamine sulfate (1.0 mg/kg), (+)-
N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine hydrochloride
((+)-MBDB; 1.75 mg/kg), 5-methoxy-6-methyl-2-aminoindan
hydrochloride (MMAI; 1.71 mg/kg), (+)-lysergic acid diethylamide
tartrate (LSD; 0.08 mg/kg), and (()-1-(2,5-dimethoxy-
4-iodophenyl)-2-aminopropane hydrochloride (DOI; 0.40 mg/
kg). All drugs were dissolved in 0.9% saline and were injected
intraperitoneally in a volume of 1 mL/kg, 30 min before the
sessions.
None of the rats had previously received drugs or behavioral
training. Water was freely available in the individual home
cages, and a rationed amount of supplemental feed (Purina
Lab Blox) was made available after experimental sessions to
maintain approximately 80% of free-feeding weight. Lights
were on from 0700 to 1900. The laboratory and animal facility
temperature was 22-24 °C, and the relative humidity was 40-
50%. Experiments were performed between 0830 and 1700
each day, Monday through Friday.
Six standard operant chambers (model E10-10RF, Coulbourn
Instruments, Lehigh Valley, PA) consisted of modular
test cages enclosed within sound-attenuated cubicles with fans
for ventilation and background white noise. A white house
light was centered near the top of the front panel of the cage,
which was also equipped with two response levers, separated
by a food hopper (combination dipper pellet trough, model E14-
06, module size 1/2), all positioned 2.5 cm above the floor. Solidstate
logic in an adjacent room, interfaced through a Med
Associates interface to a 486-based microcomputer, controlled
reinforcement and data acquisition with locally written software.
Briefly, a fixed ratio (FR) 50 schedule of food reinforcement
(Bioserv, 45 mg of dustless pellets) in a two-lever paradigm
was used. At least one drug and one saline session separated
each test session. Rats were required to maintain an 85%
correct responding criterion on training days in order to be
tested. In addition, test data were discarded when the
accuracy criterion of 85% was not achieved on the two training
sessions following a test session. Test sessions were run under
conditions of extinction, with rats removed from the operant
chamber when 50 presses were emitted on one lever. If 50
presses on one lever were not completed within 5 min, the
session was ended and scored as a disruption. Treatments
were randomized at the beginning of the study.
In Vitro [3H]-5-HT and [3H]DA Uptake Inhibition. The
procedure of Steele et al.22 was employed with minor modifications
exactly as described previously.16 Briefly, three rats were
decapitated and their brains rapidly removed and dissected
over ice. The cerebellums were removed and discarded, and
the remaining brain tissue (ca. 4 g, wet weight) was pooled,
diced, and homogenized in 20 mL of ice-cold 0.32 M sucrose.
Homogenizations were done in a prechilled Potter-Elvehjem
tissue grinder with a motor-driven Teflon pestle at 0 °C, for
two periods of 1 min each, 6 strokes/min, with a 15-s interval
between periods. The tissue homogenate was subjected to
centrifugation (Beckman J2-21 with JA-20 rotor; 4 °C) at 1090g
for 10 min. The pellet was discarded, and the supernatant
was subjected to centrifugation at 17400g for 30 min. The
resulting pellet was resuspended with a polytron (setting 5,
20 s; Kinematica) in 30-40 mL of ice-cold, aerated (5% CO2
in O2) modified Krebs-Ringer bicarbonate (KR) buffer containing
the following (mM): NaCl (124.3), KCl (2.95), MgSO4
(1.30), KH2PO4 (1.25), NaHCO3 (26.0), CaCl2 (2.41), d-glucose
(10.4), Na2EDTA (0.03), and Na ascorbate (0.06), pH 7.4-7.6.
The synaptosomal suspension was stored on ice until use.
The ability of synaptosomes to accumulate tritiated serotonin
([3H]-5-HT), dopamine ([3H]DA), and norepinephrine
([3H]NE) was measured in the absence and presence of various
concentrations of test drugs as follows: a 200-ÌL aliquot of
the synaptosomal suspension was added to test tubes containing
1.65 mL of ice-cold KR buffer, 50 ÌL of test drugs (dissolved
in deionized water) or deionized water (for total and nonspecific
determinations), and 50 ÌL of pargyline HCl solution (final
concentration, 100 ÌM). The test tubes were preincubated in
an aerated (5% CO2 in O2) 37 °C shaking water bath for 5 min.
The tubes were then returned to the ice bath and chilled for
10-15 min. Tritiated neurotransmitter (New England Nuclear)
was added (50 mL of stock solution; final concentration, 10
nM), giving a final incubation volume of 2 mL. All tubes except
nonspecific assays were returned to the aerated 37 °C shaking
water bath for 5 min to initiate neurotransmitter uptake.
1004 Journal of Medicinal Chemistry, 1998, Vol. 41, No. 6 Notes
Uptake was terminated by chilling the test tubes in an ice bath
and then rapidly filtering them through glass fiber filters
(Whatman GF/C) pretreated with 0.05% poly(ethylenimine)
using a 24-well cell harvester (Brandel). Filters were washed
with 2 3 mL of ice-cold KR buffer, allowed to air-dry for 10
min, and then placed in plastic liquid scintillation vials.
Scintillation cocktail (10 mL of Ecolite; ICN Biomedicals) was
added, and the vials were sealed, vortexed, and allowed to
stand overnight. Radioactivity was measured using liquid
scintillation spectroscopy (Packard model 4430). Specific
uptake was defined as uptake at 37 °C minus uptake at 0 °C,
in the absence of drugs. IC50 values were calculated from at
least three experiments, each done in triplicate.
Statistical Analysis. Data from the drug discrimination
studies were scored in a quantal fashion, with the lever on
which the rat first emitted 50 presses in a test session scored
as the "selected" lever. The percentage of rats selecting the
drug lever (% SDL) for each dose of compound was determined.
The degree of substitution was determined by the maximum
% SDL for all doses of the test drug. No substitution (NS) is
defined as 59% SDL or less, and partial substitution is 60-
79% SDL. If the compound was one that completely substituted
for the training drug (at least one dose resulted in a %
SDL ) 80% or higher), the ED50 values and 95% confidence
intervals (95% CI) were then determined from quantal doseresponse
curves according to the procedure of Litchfield and
Wilcoxon.23 If the percentage of rats disrupted (% D) was 50%
or higher, the ED50 value was not determined, even if the %
SDL of nondisrupted animals was higher than 80%.
In vitro data were transformed from dpm to percent inhibition
of specific uptake and analyzed using the computer
program PRISM,24 from which the IC50 values (nM) were
calculated. The IC50 values reported are the mean ( SEM
from three or four experiments run in triplicate with 9 or 10
concentrations of test drugs.
Materials. (S)-(+)-Amphetamine sulfate was purchased
from Smith Kline & French Laboratories (Philadelphia, PA).
Pargyline hydrochloride was purchased from Sigma (St. Louis,
MO). (S)-(+)-MBDB, MMAI, and (()-DOI, as their hydrochlorides,
were synthesized in our laboratory.4,25,26 (+)-LSD
tartrate was obtained from NIDA. For drug discrimination
experiments, all drugs were dissolved in 0.9% saline and
injected intraperitoneally in a volume of 1 mL/kg, 30 min
before the session.
Acknowledgment. This work was supported by
NIH Grant DA-04758 from the National Institute on
Drug Abuse. M. Parker was supported by a National
Institutes of Health-National Institute of General
Medical Sciences Predoctoral Training Grant.
References
(1) E. Merck Company in Darmstadt. Verfahren zur Darstellung
von Alkyloxyaryl-, Dialkyloxyaryl- und Alkylendioxyarylaminopropanen
bzw. deren am Stickstoff monoalkylieren Derivaten.
German Patent No. 274,350, Dec. 24, 1912; Chem. Abstr. 8, 3350.
(2) Nichols, D. E.; Glennon, R. A. Medicinal Chemistry and Structure
Activity Relationships of Hallucinogens. In Hallucinogens:
Neurochemical, Behavioral, and Clinical Perspectives; Jacobs,
B. L., Ed.; Raven Press: New York, 1984.
(3) Shulgin, A. T. The Background and Chemistry of MDMA. J.
Psychoact. Drugs 1986, 18, 291-304.
(4) Nichols, D. E.; Hoffman, A. J.; Oberlender, R. A.; Jacob, P., III;
Shulgin, A. T. Derivatives of 1-(1,3-Benzodioxol-5-yl)-2-
butanamine: Representatives of a Novel Therapeutic Class. J.
Med. Chem. 1986, 29, 2009-2015.
(5) Titeler, M.; Lyon, R. A.; Glennon, R. A. Radioligand Binding
Evidence Implicates the Brain 5-HT2 Receptor as a Site of Action
for LSD and Phenylisopropylamine Hallucinogens. Psychopharmacology
1988, 94, 213-216.
(6) Johnson, M. P.; Conarty, P. F.; Nichols, D. E. [3H]monoamine
Releasing and Uptake Inhibition Properties of 3,4-Methylenedioxyamphetamine
and p-Chloroamphetamine Analogues. Eur.
J. Pharmacol. 1991, 200, 9-16.
(7) Nichols, D. E.; Marona-Lewicka, D.; Huang, X.; Johnson, M. P.
Novel Serotonergic Agents. Drug Des. Discovery 1993, 9, 299-
312.
(8) Marona-Lewicka, D.; Nichols, D. E. The Effect of Selective
Serotonin Releasing Agents in the Chronic Mild Stress Model
of Depression in Rats. Stress.
(9) McKenna, D. J.; Guan, X.-M.; Shulgin, A. T. 3,4-Methylenedioxyamphetamine
(MDA) Analogues Exhibit Differential Effects
on Synaptosomal Release of 3H-Dopamine and 3H-5-
Hydroxytryptamine. Pharmacol. Biochem. Behav. 1991, 38,
505-512.
(10) Barfknecht, C. F.; Nichols, D. E.; Dunn, W. J., III. Correlation
of Psychotomimetic Activity of Phenethylamines and Amphetamines
with 1-Octanol-Water Partition Coefficients. J. Med.
Chem. 1975, 18, 208-210.
(11) Nichols, D. E.; Brewster, W. K.; Johnson, M. P.; Oberlender, R.;
Riggs, R. M. Nonneurotoxic Tetralin and Indan Analogues of
3,4-(Methylenedioxy)amphetamine (MDA). J. Med. Chem. 1990,
33, 703-710.
(12) Shulgin, A.; Shulgin, A. PIHKAL; Transform Press: Berkeley,
CA, 1991; pp 710-711; ISBN 0-9630096-0-5.
(13) Comins, D. L.; Brown, J. D. Ortho Metalation Directed by
R-Amino Alkoxides. J. Org. Chem. 1984, 49, 1078-1083.
(14) Shulgin, A.; Shulgin, A. PIHKAL; Transform Press: Berkeley,
CA, 1991; p 709; ISBN 0-9630096-0-5.
(15) Sinhababu, A. K.; Ghosh, A. K.; Borchardt, R. T. Molecular
Mechanism of Action of 5,6-Dihydroxytryptamine. Synthesis and
Biological Evaluation of 4-Methyl, 7-Methyl, and 4,7-Dimethyl-
5,6-dihydroxytryptamines. J. Med. Chem. 1985, 28, 1273-1279.
(16) Monte, A. P.; Marona-Lewicka, D.; Cozzi, N. V.; Nichols, D. E.
Synthesis and Pharmacological Examination of Benzofuran,
Indan, and Tetralin Analogues of 3,4-(Methylenedioxy)amphetamine.
J. Med. Chem. 1993, 36, 3700-3706.
(17) Monte, A. P.; Marona-Lewicka, D.; Parker, M. A.; Wainscott, D.
B.; Nelson, D. L.; Nichols, D. E. Dihydrobenzofuran Analogues
of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)
alkylamine Derivatives with Rigidified Methoxy Groups.
J. Med. Chem. 1996, 39, 2953-2961.
(18) Johnson, M. P.; Nichols, D. E. Combined Administration of a
Nonneurotoxic 3,4-Methylenedioxymethamphetamine Analogue
with Amphetamine Produces Serotonin Neurotoxicity in Rats.
Neuropharmacology 1991, 30, 819-822.
(19) Nichols, D. E. Role of Serotonergic Neurons and 5-HT Receptors
in the Action of Hallucinogens. In Handbook of Experimental
Pharmacology. Serotoninergic Neurons and 5-HT Receptors in
the CNS; Baumgarten, H. G., Gothert, M., Eds.; Springer-Verlag
GmbH & Co.: Heidelberg, Germany, 1997, in press.
(20) Nichols, D. E.; Johnson, M. P.; Oberlender, R. 5-Iodo-2-aminoindan:
A nonneurotoxic analogue of p-iodoamphetamine. Pharmacol.
Biochem. Behav. 1991, 38, 135.
(21) Huang, X.; Marona-Lewicka, D.; Nichols, D. E. p-Methylthioamphetamine
Is a Potent New Nonneurotoxic Serotonin-Releasing
Agent. Eur. J. Pharmacol. 1992, 229, 31-38.
(22) Steele, T. D.; Nichols, D. E.; Yim, G. K. W. Stereochemical Effects
of 3,4-Methylenedioxymethamphetamine (MDMA) and Related
Amphetamine Derivatives on Inhibition of Uptake of [3H]-
monoamines into Synaptosomes from Different Regions of Rat
Brain. Biochem. Pharmacol. 1987, 36, 2297.
(23) Litchfield, J. T.; Wilcoxon, F. A. Simplified Method of Evaluating
Dose-Effect Experiments. J. Pharmacol. Exp. Ther. 1949, 96,
99-113.
(24) GraphPad Software Inc., San Diego, CA.
(25) Johnson, M. P.; Frescas, S. P.; Oberlender, R.; Nichols, D. E.
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. 1991, 34, 1662-1668.
(26) Mathis, C. A.; Hoffman, A. J.; Nichols, D. E.; Shulgin, A. T.
Synthesis of High Specific Activity 125I and 123I-Labeled Enantiomers
of 2,5-Dimethoxy-4-iodophenylisopropylamine (DOI). J.
Labeled Compd. Radiopharm. 1988, 25, 1255-1265.
JM9705925
Notes Journal of Medicinal Chemistry, 1998, Vol. 41, No. 6 1005

[Alfa]

http://www.nida.nih.gov/pdf/monographs/94.pdf

[anj0vis]

This
paper is one of the first to study MDMAI and MDAI. They conclude that
they almost fully substitute for MDMA and show less signs of
neurotoxicity. This is also the paper where I tracked down the
synthesis, although it is rather short and leaves lots of stuff as
references to other works.

(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative
stimulus in studies of 3,4-methylenedioxy-methamphetamine-like behavioral
activity

R Oberlender and DE Nichols


Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and
Pharmacal Sciences, Purdue University, West Lafayette, Indiana.






The stimulus properties of 3,4-methylenedioxymethamphetamine (MDMA)- like
compounds were studied in rats trained to discriminate saline from
(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine [(+)-MBDB] hydrochloride
(7.18 mumol/kg; 1.75 mg/kg), the alpha-ethyl homolog of MDMA. In previous
experiments with (+)-MBDB as a test drug, complete substitution was
observed for MDMA but not for (+)-lysergic acid diethylamide or
(+)-amphetamine. In the study reported here, the (+)- MBDB cue generalized
to MDMA and the parent drug, 3,4- methylenedioxyamphetamine. All three
drugs exhibited a similar stereoselectivity, the (+)-isomer having potency
greater than the (-)- isomer. By contrast, the hallucinogens, (+)-lysergic
acid diethylamide, 2,5-dimethoxy-4-methylamphetamine and mescaline and the
psychostimulants (+)-amphetamine and (+)-methamphetamine did not substitute
for (+)-MBDB. Cocaine produced partial substitution. The results support
the hypothesis that the primary behavioral activity of MDMA-like compounds
is unlike that of hallucinogens and stimulants and may represent the
effects of a novel drug class, given the name entactogens. Although the
mechanism of action for the discriminative stimulus properties of MDMA-like
compounds is not known, there is evidence that presynaptic serotonergic,
but not dopaminergic, mechanisms are critical. Finally,
5,6-methylenedioxy-2-aminoindan a non- neurotoxic
3,4-methylenedioxyamphetamine rigid analog that was previously found to
substitute for MDMA but not for (+)-lysergic acid diethylamide was found in
the study described here to substitute completely for (+)-MBDB. The
N-methyl derivative 5,6-methylenedioxy-2- methylminoindan produced similar
results. The demonstration of entactogen-like discriminative stimulus
properties, for drugs devoid of neuronal degenerative toxicity potential,
serves as evidence of the independent mechanisms for these effects in rats.

[anj0vis]

This paper is also of interest here (Erowid library http://www.erowid.org/references/refs_view.php?ID=816). I hastily mixed this and paper I posted above, so here is the short description of the synthesis, albeit non-complete:
Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA)
Nichols DE, Brewster WK, Johnson MP, Oberlender R, Riggs RM
J Med Chem, 1990; 33(2):703-10

Four cyclic analogues of the psychoactive phenethylamine derivative 3,4-(methylenedioxy)amphetamine were studied. These congeners, 5,6- and 4,5-(methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and 5,6-(methylenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Two groups of rats were trained to discriminate either LSD tartrate (0.08 mg/kg) from saline, or (+/-)-MDMA.HCl (1.75 mg/kg) from saline. In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine 1-(2,5-dimethoxy-4- methylphenyl)-2-aminopropane (DOM) were also evaluated. None of the methylenedioxy compounds substituted in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained rats. Compounds 4a and 4b did not substitute in MDMA-trained rats. 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. In view of the now well-established serotonin neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue 1, 3a and 3b were evaluated and compared to 1 for similar toxic effects following a single acute dose of 40 mg/kg sc. Sacrifice at 1 week showed that neither 3a nor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA levels nor were the number of binding sites (Bmax) depressed for [3H]paroxetine. By contrast, and in agreement with other reports, 1 significantly depressed all three indices of neurotoxicity. These results indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but that they lack similar serotonin neurotoxicity.
----------
there was also one study where MMAI was found to be dysphoric to rats (place aversion for place-administration association test), MDAI was found to be more or less neutral, MBDB slightly euphoric and MDMA the most euphoric. I try to locate that article from my files somewhere, but this was somewhat disappointing considering that MDAI seemed to fully substitute for MDMA in some other tests. Perhaps MDMAI would be better. Still, I'd like to bioessay MDAI to see how it differs from MDMA. We'll see if we ever get to see that produced anywhere.

[moeBius]

i had the luck to obtain some mbdb containing tabs around 4 years ago. it's quite a nice substance, does not cause such a strong buzz like mdma and is less energizing.

[fastandbulbous]

2-aminoindan is AKA MMAI


It isn't, MMAI is 5-methoxy-6-methyl-2-aminoindan and is a potent 5HT releasing drug, whereas 2-aminoindan is dopaminergic in action, being a stimulant and quite an effective analgesic.


While MMAI and 2AI are as yet uncontrolled just about everywhere MBDB is covered by the phenethylamine derivatives paragraph of the Misuse of Drugs Act, making it a schedule 1, class A drug in the UK

[whiteglovesman]

There seems to be little to no information on 2-aminoindan on the net.

SWIM has recently ordered 1 gram of this substance and will post a full report of it once it arrives.

If anyone does have any experience of it and can give some insights into the effects SWIM would be very grateful.

[whiteglovesman]

ok i can confirm this substance has little to no effect.

i have ingested and insuffulated loads...

it's worthless..

internet headshops are touting this as an xtc alternative..

lies.. you will become more high off of a bowl of cornflakes..

save your money and your time..

wgm.

[slotty]

wgm,swik have obtained 1gram of 2indanamine hydrochloride,which as yet is legal but untested.Is it the same as the stuff you had.Does anyone know what it is before i test it.

[Nagognog2]

Congeners and such, well written above, tell a long story that seems to say it is not worth persuing. Interestesting in small amounts - but few who would bother a second trial.

Be very careful. It does not seem to become better with higher quantity. Read up and tell SWIM to use extreme caution.

[slotty]

Thanks.Swim tried it.Small ammount (few grains)bombed.A small sense of well being.More tried an hr later,swim just became agitated.and forgetful.swim will leave alone for now,until more research has been done.

[Psych0naut]

From the few experience reports SWIM could find about 2-Amino-indan, SWIM noticed one needs to administer it I.M, to get full effects out of it.

[enquirewithin]

Originally Posted by Psych0naut

From the few experience reports SWIM could find about 2-Amino-indan, SWIM noticed one needs to administer it I.M, to get full effects out of it.

Are the full effects pleasant?

[Psych0naut]

A experience report with 50mg I.M.:

Artificial intelligence. Thats what we call 2-AI around here.. After reading all the hyped up reports we bought 10G only to be dissapointed with oral and intranasal use. Recently reports of IV use of 2-AI emerged. Only having minor prior experience with the needle I decided to use it in my muscle rather than vein. I weighed out 100mg of the powder and seperated it into two piles. The powder readily dissolved in .2 CC's of distilled water. Next I shot it into the side of my leg.

About 10-15 minutes later I was very impressed with the effects. A very nice stimulation and pleasant state of mind soon began. My mouth dried up and I had a tight feeling in my chest, that is characteristic of my bodies reaction to amphetamines. I had a 3 hour car ride ahead and it made it enjoyable. This is apparently the best way to administer 2-AI. Little to no comedown or after effects.

I found 40mg orally to produce too much anxiety. 20mg intranasal produced little if no effects.

Source: Erowid experience report

[enquirewithin]

Curious. As this was IM, it would proably be effective plugged as well-- if anyone wanted to go there!

[radiometer]

About 10-15 minutes later I was very impressed with the effects. A very nice stimulation and pleasant state of mind soon began. My mouth dried up and I had a tight feeling in my chest, that is characteristic of my bodies reaction to amphetamines. I had a 3 hour car ride ahead and it made it enjoyable.

Many might report such from a couple cups of coffee, except for noting a need to stop and pee a couple of times.