• N&PD Moderators: Skorpio | thegreenhand

  • Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

Neurotoxicity of p-haloamphetamines

Smyth

Smyth

Bluelighter
Joined
Nov 10, 2004
Messages
2,157
It is well known that serotonergic affinity increases and dopaminergic activity decreases as you move down the series of p-halogenated amphetamines.

However, why is the same assumed to be the case for neurotoxicity? eg:

http://en.wikipedia.org/wiki/4-Fluoroamphetamine

I was reading the following article recently (see introduction):

http://www.ncbi.nlm.nih.gov/pubmed/8749023
http://www.sendspace.com/file/uial1u

It seems p-iodoamphetamine is LESS (not more) neurotoxic than the p-chloro analog.
 
Hammilton said:
yeah, but only para-fluoro isn't neurotoxic.
Click to expand...

Really? Do you mean completely non neurotoxic or minimally?
Wiki states that it is somehow neurotoxic, do you have any reference to your claim?

Also would the drug itself or its metabolites have the same toxicity issues as methyldopamine has? The fluoro would avoid hydroxylation of the 4th position though hydroxylation at the 3rd position could stil occur and I wonder if such a metabolite would act similarly to methyldopamine.

Based on your knowledge would you consider 4-FA less neurotoxic (or generally safer than amphetamine and methamphetamine?
 
^I think it still is, but much less than, for example, the p-Cl or p-Br. The p-Me isn't specifically listed as such but the reports certainly do make it sound so... proof of the pudding being in the eating and so on. I know a couple of people who were very impressed with the m-Me analogue of mephedrone. I suspect because it's more like plain amphetamine... but it's just that; a suspicion.
 
Last edited:
pretty sure it was a nichols study that found 4-FA to be non-neurotoxic, but someone else will chime in.
 
This could be the answer:

Neuropharmacology (1975), 14(10): 739
The ability of 4-chloroamphetamine, 4-bromoamphetamine, and 4-fluoroamphetamine to deplete brain 5-hydroxyindoles and some pharmacokinetic properties of these drugs were compared in rats. Half-lives of the three compounds in rat brain were 3.7, 4.4, and 5.7 hr, respectively for the 4-fluoro, 4-chloro, and 4-bromo amphetamines. The tendency of the drugs to be associated with particulate material in brain homogenates or to prefer an organic versus an aqueous phase in uitro varied in the order 4-bromo > 4-chloro > 4-fluoro. This order of activity also applied to the inhibition of monoamine oxidase in vitro. All three 4-haloamphetamines reduced the activity of tryptophan hydroxylase and lowered the levels of serotonin and 5-hydroxyindoleacetic acid in whole brain initially. With 4-chloroamphemine and 4-bromoamphetamine, the depletion of brain 5-hydroxyindoles lasted for at least a week. 4-Fluoroamphetamine, in contrast, lowered serotonin and 5-hydroxyindoleactic acid levels only for short times (2-6 hr) after drug injection, and 5-hydroxyindole levels were essentially back to normal within 24 hr. Prior treatment with an uptake inhibitor prevented the serotonin depletion by all of the haloamphetamines, indicating they all required the membrane uptake pump for entry into the neurone. The effect of 4-bromoamphetamine, like that of 4-chloroamphetamine, could be reversed by subsequent injection of the uptake inhibitor after short periods but not after 24-48 hr. The failure of 4-fluoroamphetamine to produce a long-lasting depletion of brain serotonin like that produced by 4-chloroamphetamine or 4-bromoamphetamine may reflect the inability of the fluoro-compound to be metabolized in the same way as the other haloamphetamines.​


I think that ALL amphetamines are neurotoxic to some degree, depending on dosage and frequency of usage, of course. But the 4-F-derivative stands far behind 4-Cl/4-Br/4-I/4-Me with respect to brain damaging effects. Its's all relative, isn't it. Or in Paracelcus' famous words: „Dosis sola facit venenum“ :)
 
Last edited:
Well yes and I have a feeling it has been made and tested already though I would suspect higher toxicity from it, the serotonergic boom would be quite fucking high IMO.
However this is simply my suspicion so I'll wait for someone more qualified to give an opinion.
 
Trifluoromethyl is bioisoteric to methyl, hence I think 4-CF3-amphetame would be in the same ballpark like PMA.
 
^
Except that CF3 is a strong electron withdrawing group, while plain CH3 is different. How much does an electronegativity of the group contributes to binding here?
 
And PMA contains a methoxy group not a methyl, the hydrogen bonding seems to be important for anti-MAO activity.
 
pretty sure it was a nichols study that found 4-FA to be non-neurotoxic, but someone else will chime in.
Click to expand...

Correct. It was found non-neurotoxic in comparison with MDMA, just as methylone has been. The study was conducted either in 1999 or 2001.

ebola
 
ebola? said:
Correct. It was found non-neurotoxic in comparison with MDMA, just as methylone has been. The study was conducted either in 1999 or 2001.

ebola
Click to expand...

I wonder how much data there is on 2-fluoroamphetamine in terms of neurotoxicity as compared to dextroamphetamine/4-fluoroamphetamine/3-fluoroamphetamine/methamphetamine. I haven't found specific IC50 values and am also interested in comparing this to other stimulants. 3-FA is definitely a very potent dopamine releasing agent, and I'm assume 2-FA would even have more affinity for DA/NE? That would just be ridiculuous. However, people have found 2-FA to require pretty high doses, so mg to mg it doesn't seem as potent. 2-FA also seems to be a TAAR1 agonist, I wonder if 3-FA/4-FA share this property. 2-FA would probably lead to more DA receptor down-regulation and perhaps DAT density loss than 3-FA/2-FA but might not share their potent serotonin releasing properties, and we know DA/5-HT dual releasers have a synergistic tendency to be neurotoxic, might make 2-FA slightly safer.

I hope eventually we can compile a larger list of binding affinities that includes the halogenated amphetamines, 2-diphenylmethylpiperidine, methylenedioxypyrovaleroneetc, prolintane, pyrovalerone, alpha-pyrrolidinopropiophenone, halogenated methcathinones, etc... excluding 4-MMC for purposes of distaste :X

http://i249.photobucket.com/albums/gg223/antec6/stimtable.png

I found this in another thread:

3-FA
EC50 NE release (nM) 16.1 ± 1.7
EC50 DA release (nM) 24.2 ± 1.1
EC50 5HT release (nM) 1,937 ± 202

Is that EC50 for DA release correct? It doesn't seem that potent as compared to d-amp then? Something doesn't look right. I also wonder how dosage affects the release/re-uptaking inhibition ratios, contrary to what most people think, I believe dextroamphetamine does not display releasing properties at low dosages, maybe a little NE releasing, but that's about it, it is pretty much a re-uptake inhibitor, but then again recreational doses would have potent NE releasing properties and some DA as well. I calculated the average threshold dose to be around 20 mg d-amp, but that would vary depending on tolerance and other factors.

"In contrast, in the absence of a cytoplasmic NE pool, low doses of the AMPH derivatives act predominantly as uptake blockers at the neuronal transporter. However, as the dose is increased, the AMPH derivatives can accumulate in the cytoplasm to sufficiently high concentrations to disrupt vesicular storage, thus facilitating transmitter release from all three biogenic amine nerve terminals" - http://www.jneurosci.org/content/15/2/1308.full.pdf

I've also have the PDF: Comparison of the Effects of the Isomers of Amphetamine, Methylphenidate and Deoxypipradrol on the Uptake of /-[3H]Norepinephrine and [3H]Dopamine by Synaptic Vesicles from Rat Whole Brain, Striatum and Hypothalamus, if anyone is interested
 
Last edited:
Is that EC50 for DA release correct? It doesn't seem that potent as compared to d-amp then? Something doesn't look right.
Click to expand...

Do remember that 3-fa is a racemate, D-amp is one isomer and so it's probably more effective.

I have yet to see EC50's for single isomers of the fluoroamphetamines.
 
sekio said:
Do remember that 3-fa is a racemate, D-amp is one isomer and so it's probably more effective.

I have yet to see EC50's for single isomers of the fluoroamphetamines.
Click to expand...

What would your approximations be of neurotoxicity of 2-FA/3-FA versus that of amphetamine/meth-amp/4-FA? Is it true that only the fluoro-halogenated amphetamines have the potential for reasonable toxicity using pure amp as a standard vs. other halo-amp's?
 
In my mind, the fluoroamphetamines (2,3,4) and normal dose amphetamine (<200mg) are essentially non-neurotoxic. MDMA is also reasonably safe when used in moderation.

Methamphetamine, high dose amph, and the non-fluoro-haloamphetamines (pca, pba, pia), on the other hand, are bad news bears.
 
There is a nice bit of info on this in the Shulgin Index (vol 1), but I assume a page scan would not be considered welcome here considering copyright. Anyway I am giving it as a reference then. Check the PCA entry for it, off the top of my head.
(Nice book by the way, not much of a casual read whatsoever like the anecdote/novel style first parts of XIHKALs since such a part is missing but I have found out already that not only my 2-MeA but also my 4-MeA is mainly anorexigenic - but thats offtopic)
 
Very interesting discussion.

ebola? said:
Correct. It was found non-neurotoxic in comparison with MDMA, just as methylone has been. The study was conducted either in 1999 or 2001.
ebola
Click to expand...

So if 4-FA compared to MDMA is considered non-neurotoxic at doses effective for -reasonable- recreational use, and bk-MDMA (Methylone) is considered less potent and less toxic than it's de-keto analogue..
Then I wonder.. what would happen if we substituted the flour sitting on 4'- with a bromine, added a ketone on the beta position?

The 4-bromo would most likely increase potency since it's a much heavier halogen.
This we know from comparing the potencies of the quite nasty haloamphetamines 4-chloro-A and 4-iodo-A, of which the 4-bromo is the most potent.

Now, cathinones are a little different.
They are usually considerably less potent, and have different binding affinities.
If we look to the Methylone/MDMA example it seems they are also somewhat less neurotoxic (?) than their amphetamine brethren.

We would end up with 4-bromocathinone. I am not sure if this has ever been made, but it would be interesting to see it's effects.
I know it's n-methylated brother, 4-BMC is causing quite a stir, because of speculated toxicity. But are we really that sure that they are neurotoxic?

Sure, the close relation to 4-MMC makes me think of potential vasoconstriction, but doesn't the reduced potency from the beta-ketone also mean less toxicity?
 
You must log in or register to reply here.
Top