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3,4-Difluoroamphetamin

hugo24

hugo24

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Joined
Mar 23, 2005
Messages
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A (non-accessible by privates!) supplier sells this compound for some reason.Wonder what its action might be,at least from the 4-FA analog we have no indications which would prevent tasting.A paper from Nichols covers this (if you like Drosophilas...) without giving it the kiss of death:

http://jpet.aspetjournals.org/cgi/content/full/308/2/679

But you're getting in the field of N-methyl phenyl ethanol transferase inhibitors (which I admittedly know not much about).




One (a bit funny) abstract I came across is here:

"Bibliographic Information

Synthesis of 5,6-difluoro-2-aminoindan× HCl. Ma, Eun-Sook. College of Pharmacy, Catholic University of Taegu-Hyosung, Hayang, S. Korea. Yakhak Hoechi (1999), 43(6), 751-755. Publisher: Pharmaceutical Society of Korea, CODEN: YAHOA3 ISSN: 0513-4234. Journal written in Korean. CAN 132:207623 AN 2000:22333 CAPLUS

Abstract

3,4-Difluoroamphetamine×HCl and 5,6-difluoro-2-aminoindan×HCl were synthesized as serotonergic agents. 3,4-Difluorobenzaldehyde was condensed with nitroethane and reduced with LiAlH4 to obtain 3,4-Difluoroamphetamine. 5,6-Difluoro-2-aminoindan×HCl was synthesized through reactions of condensation with malonic acid, 10% Pd-C redn., cyclization with polyphosphoric acid, oximation and catalytic hydrogenation. "

If the catholics make it,it can't be that bad...
 
3,4 Diflouro? eek, I don't think I'd be willing to test that on anything capable of walking upright.

Certainly going to be risky, imho.
 
parafluoroamphetamine is not neurotoxic in the same way as the other 4-haloamphetamines, though it has other toxic effects not far above the normal dose.
I see little reason to suspect that this difluoro compound will be neurotoxic either.
those fluorines are going to stay put, and prevent ring hydroxylation at the 3 or the 4 position, amphetamine is metabolised to a degree by oxidation at the 4 position.
however in the UK this substance as well as the single fluorinated parafluoro amphetamineis are class A controlled drugs
V
 
Yeah I see no reason why this will be hideously toxic. That said, I feel there are more worthwhile and safer things to experiment with.
 
I didn't think 4-fluoroamphetamine was particularly toxic--correct me if I'm wrong. However, with the 3-position also substituted like that, I would estimate that this is a highly serotonergic agent. All serotonin and no dopamine makes for a dull, dull amphetamine.
 
That's what I was thinking. Have any 3-halogonated amphetamines had any recreational potential?
 
Dondante-yeah its been a hard time but now I'm up and running.Just put off medication-and what I have to deal now is a distinct euphoria,what a strange withdrawal symptom!But thats stuff for the other thread.

Riemann-what makes you think the 3 position adds serotonergic action?For some reason Dopamin is 3,4 substituted,to speak a bit twisted and esoteric.Bupropion has a 3-Chloro and works on the DA and NA.The 4 Chloro on Amphetamine makes it a strong serotonin releaser,the 3-Chloroamp. to my knowledge has a broader profile SER/DA/NA,but I will search this out again.

Not that I'm particularly horny to try out the 3,4-Difluoroamphetamin,as were maybe the Koreans.Of course it should be approached with caution,not because it is expected to be neurotoxic (the chances are small as already outlined) but because of potential potent enzym inhibition properties.

Hamilton-had (m)any 3 substituted amps even been tested broadly?
 
the widely tested 3 'halo' is fenfluramine, the trifluoromethyl group is a slightly larger than bromine sized halogen isostere, slightly more electronegative and slightly more lipophilic. A neurotoxin and a potent 5-ht2b agonist, leading to pulmonary and cardiac problems. Withdrawn from the market because of damage to the valves in the heart caused by tissue growth due to 5-ht2b agonism.

I don't think there is any future in halo amphetamines however substituted.
All of them have at some point been investigated as anorectics, including the now notorious PCA. I believe that one may even have made it into humans.

I have seen quite a few reports of parafluoroamphetamine leading to toxic side effects, including hyperthermia, vomiting and other nasty effects. It gives the distinct impression that the lethal dose for this one could be quite low particularly in sensitive individuals.
 
That's right, I forgot about p-chloroamphetamine, I'm pretty sure that was tested on humans, and didn't go real well.

I suppose a di-halo amp may well not be toxic, but like I said, I'm not particularly interested in trying anything as likely to prove toxic.
 
For some reason, para-chloroamphetamine (PCA) is a highly potent serotonergic neurotoxin--far more neurotoxic than MDA/MDMA. I think it was indeed tried in humans...I really feel sorry for the poor motherfuckers that had to test this one. Strangely, the para-flouro analogue (the much-heralded 4-FA) and even the para-bromo analogue (or at least, the N-methyl-para-bromo analogue, if I remember the study correctly--it was from the 1970s) do not seem to be as potent as serotonergic neurotoxins. Doubtless, 4-fluoroamphetamine has its side effects, which sound similar to those of MDMA: nausea, hyperthermia, jaw clenching; but I've never heard of it manifesting any sort of long-term toxicity, like PCA. However since nor-fenfluramine (meta-CF3-amphetamine) is a 5-HT2B receptor agonist, causing eventual cardiac valve malfunction, I think a meta-halo amphetamine is probably not a great idea.
 
Furthering the background of the haloamps,taken from:

http://www.erowid.org/archive/rhodium/chemistry/shulgin.pea.sar.hop.html#35

Interestingly PCA is claimed to be an effective antidepressant...

"3.5.1. 4-Chlorophenylisopropylamine

The simplest of the halogenated phenylisopropylamines is 4-chlorophenylisopropylamine (79, para-chloroamphetamine, 4-CA). It and the N-methyl homolog (80) are highly active compounds in experimental animals, producing a remarkably long-lasting depletion of brain serotonin levels (Pletscher et al., 1963) and a decrease in tryptophane hydroxylase activity (Sanders-Bush et al., 1972).

Considerable clinical application of 4-CA has been made, and it has been found effective as an antidepressant when used chronically at levels of 75 mg/day (van Praag et al., 1971; van Praag and Korf, 1976). There are very few side effects noted and the drug is tolerated very well. However, indications of raphe-nucleus degeneration (Yunger et al., 1974) and related neurotoxicity (Harvey and McMaster, 1976) in experimental animals have discouraged further clinical study.

An unusual aspect of 4-CA metabolism is the reported conversion of the drug to oxygen-containing products. A phenolic product was identified by Parli and Schmidt (1975) as being 3-chloro-4-hydroxyphenylisopropylamine. This would seem to invoke the NIH shift as an explanation for the migration of the chloro atom. Even more remarkable is the report (Sherman and Gal, 1976) of the isolation of 3,4-dimethoxyphenylisopropylamine following the intraventricular injection of 4-CA. This represents the formation in vivo of a weak but accepted pressor and psychotomimetic. When the mechanism of its formation is understood, a chemical link may be at hand tying the simpler phenylisopropylamine stimulants to the methoxylated psychotomimetics. There were no reports from the clinical studies of 4-CA that suggested any psychotomimetic action.

3.5.2. 4-Chloro-N-methylphenylisopropylamine

The N-methyl homolog of 4-chlorophenylisopropylamine (80, para-chloromethamphetamine p-CMA, Ro 4-6861, S-33) was also found to be a potent and long-lasting depleter of brain serotonin (Fuller et al., 1965). It has been compared with methamphetamine in normal subjects (Verster and van Praag, 1970) and has been evaluated clinically in comparison with 4-CA (79) as an antidepressant (Deniker et al., 1971; van Praag et al., 1971; van Praag and Korf, 1976). Typical dosages were between 60 and 90 mg/day, administered chronically for several weeks. There appeared to be no physical or psychic dependence developed, no cardiovascular complications, and no sleep or appetite problems. There was no mention made of mental disturbances that might be considered psychotomimetic.

The alpha,alpha-dimethylphenylethylamine homologs of p-CMA have been explored clinicaly as anorexics. 4-Chloro-alpha-alpha-dimethylphenethylamine is used therapeutically under the name of Chlorphentermine; the ortho-isomer is known as Clortermine.

3.5.3. 4-Bromo-N-methylphenylisopropylamine

The bromo-counterparts of the chlorophenylisopropylamine have been studied, but have not found extensive clinical evaluation. The primary amine 4-bromophenylisopropylamine (4-bromoamphetamine) is, like the 4-chloro-analog 4-CA (79), a long-term depleter of serotonin in the brain (Fuller et al. (1975). The 4-fluoro analog, while still effective biochemically, is not of as long a duration of action. The N-methyl homolog of 4-bromo-phenylisopropylamine has demanded interest from a separate point of view, however. This compound, 4-bromo-N-methylphenylisopropylamine (81, V-111, p-bromomethamphetamine), has been found to give pharmacological profiles in a large number of animal species, which are indistinguishable from those shown by LSD and other psychotomimetics (Knoll et al., 1970). Although much of the literature appearing over the period from 1965 to 1975 refers to (81) as a psychotomimetic, it had apparently never been clinically assayed in man. It is now known that the compound "has no psychotomimetic effect whatsoever in humans" (Knoll, 1974, personal communication). The high pharmacological potency of (V-111) in the biochemistry of serotonin and its apparent enhancement of learning and memory in experimental animals have maintained an active interest in it in the research area."
 
Serotonin

Apologies for the necropost...

According to this Nichols paper, 3,4-difluoroamphetamine has the following profile with respect to human serotonin transporters (lower number indicates higher activity):

Code: 
               hSERT       I167L       A169D       F170I       I172M       S174M 
3,4-diCl-A   130 ± 10     40 ± 10     20 ± 4      90 ± 40    240 ± 70    700 ± 20 
[B]3,4-diF-A   5600 ± 200  3900 ± 80    400 ± 200  3700 ± 1400 2800 ± 70  11000 ± 700[/B] 
MDA          700 ± 100   500 ± 200   200 ± 10    500 ± 10   2600 ± 600  2400 ± 300 
MDMA        1600 ± 500   300 ± 70    200 ± 80    600 ± 90   2000 ± 500  3700 ± 200 
diF-MDA     1200 ± 200   900 ± 200   200 ± 40   1100 ± 50   2400 ± 300  2600 ± 100 
2-Me-MDA     700 ± 200   400 ± 60    200 ± 60    400 ± 100  1300 ± 30   1000 ± 80 
5-Me-MDA     900 ± 70    500 ± 90    600 ± 40    600 ± 80   1300 ± 500  3000 ± 500 
6-Me-MDA    2200 ± 600  1400 ± 500  3100 ± 800  2200 ± 700 10000 ± 600  4500 ± 900
4-F3Me-FMA   600 ± 70    300 ± 70    100 ± 40    500 ± 60    600 ± 100  1400 ± 200
MMAI         600 ± 200   500 ± 200   400 ± 100   600 ± 200   700 ± 300  3100 ± 300

I'm going to be frank - I have no idea what the numbers mean for the different types of hSERT. But it appears that 3,4-difluoroamphetamine doesn't have much effect on serotonin, at least compared to MDxA.

I can't find any numbers with respect to its effects on dopamine, but it seems likely that it has a similar action to 3- and 4-FA, and possibly MDA.

The main thing I would be worried about is the lack of enzymatic breakdown as suggested by hugo24 (then again, that might be a good thing).

Any other neurotoxic effects likely to come into play here?
 
^^^

The smaller the number, the higher affinity it has at the serotonin transporter. Left hand column is normal human transporter, the others are mutant versions which you don't need to worry about.

Main take home message is that 3,4-DFA is pretty weak at SERT compared to most of the other drugs tested, weaker than 6-methyl-MDA which is known to be inactive in humans. As an aside I'm pretty sure someone on the Hive reported testing 3,4-DFA years ago and said it had minimal positive effects but still had a nasty comedown, and was generally not worth the bother.

On the other hand that Nichols paper has a few novel compounds I'd not come across binding numbers for before, wonder what (S)-MMMA, AEMMA or even DCPP are like, probably nowhere near as good as this makes them look on paper...
 
Thanks mad_scientist. That's settled then.

Looks like somewhere between diF and diCl the magic happens... =)
 
The only one to care about is the hSERT column, that's wild-type...

They are probably affinities, which relate to the amount of drug that must be added to displace some other high affinity ligands from the receptor.

http://www.bio.davidson.edu/people/jowilliamson/Techniques/Protocolweek8.html

Lower is better, these all tend to be competitive inhibitors

the widely tested 3 'halo' is fenfluramine, the trifluoromethyl group is a slightly larger than bromine sized halogen isostere, slightly more electronegative and slightly more lipophilic. A neurotoxin and a potent 5-ht2b agonist, leading to pulmonary and cardiac problems. Withdrawn from the market because of damage to the valves in the heart caused by tissue growth due to 5-ht2b agonism.

I don't think there is any future in halo amphetamines however substituted.
All of them have at some point been investigated as anorectics, including the now notorious PCA. I believe that one may even have made it into humans.
Click to expand...
This is an old post, but it's very well known now (and even then) that trifluoromethyl and fluoro substituents behave very differently from the heavier halogens for whatever reason (perhaps it has to do with the heavily electron withdrawing effect on the ring system, I'm not sure). We know that 4-F-amphetamine is not a neurotoxin and from the above it's clear it (3,4-DiF) doesn't have a huge affinity for SERT.

Affinity for SERT has pretty much nothing to do with abuse potential in my opinion, though.
 
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