Am I blind or are they unknown?
Am I blind or are they unknown?
I'd wager the majority of it would be excreted unchanged, while the main metabolite would be 4-Fluoro-norephedrine (hydroxyl in the beta position).
http://www.ncbi.nlm.nih.gov/pubmed/3707603Metabolic activation of the serotonergic neurotoxin para-chloroamphetamine to chemically reactive intermediates by hepatic and brain microsomal preparations.
Miller KJ, Anderholm DC, Ames MM.
Para-chloroamphetamine (PCA) is selectively toxic to serotonergic neurons in laboratory animals. Acute, reversible neurotoxicity is followed by long-term effects which include inactivation of tryptophan hydroxylase and destruction of neurons. We have studied the metabolic formation of reactive intermediates that might be involved in long-term PCA neurotoxicity. Incubation of [3H]PCA with rat hepatic microsomes resulted in NADPH-dependent and oxygen-dependent covalent binding of radioactivity to microsomal protein. Addition of SKF-525A and glutathione to incubation mixtures inhibited [3H]PCA covalent binding 30% and 92% respectively. No inhibition of radiolabeled covalent binding was observed in an atmosphere of carbon monoxide/oxygen (80/20). 7,8-Benzoflavone was more effective than metyrapone in inhibiting [3H]PCA covalent binding. The extent of [3H]PCA covalent binding to microsomal protein was unchanged after phenobarbital pretreatment of rats, whereas 3-methylcholanthrene pretreatment increased [3H]PCA covalent binding (175. NADPH-dependent and oxygen-dependent covalent binding of radioactivity was also observed when [3H]PCA was incubated with rat brain microsomal preparations. Addition of SKF-525A and glutathione to incubation mixtures inhibited covalent binding 10 and 40% respectively. There were no significant differences in total, NADPH-independent or NADPH-dependent covalent binding of radiolabeled R,S(+/-)-, R(-)-, or S(+)-PCA to rat hepatic microsomal protein. Less covalent binding was observed when [3H]amphetamine was incubated with rat liver microsomal preparations as compared to results with [3H]PCA. Minimal covalent binding was observed when [3H]PCA was incubated with liver microsomal preparations from rabbits, a species resistant to PCA neurotoxicity. Results of these metabolism studies are consistent with the hypothesis that oxidative metabolic activation of PCA to reactive and toxic metabolites is related to the long-term neurotoxicity of this agent.
http://www.ncbi.nlm.nih.gov/pubmed/1196472Comparison of 4-chloro-, 4-bromo- and 4-fluoroamphetamine in rats: Drug levels in brain and effects on brain serotonin metabolism
R. W. Fuller, J. C. Baker, K. W. Perry and B. B. Molloy
The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46206, USA
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 paniculate material in brain homogenates or to prefer an organic versus an aqueous phase in vitro 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-chloroamphetamine and 4-bromoamphetamine, the depletion of brain 5-hydroxyindoles lasted for at least a week. 4-Fluoroamphetamine, in contrast, lowered serotonin and 5-hydroxyindoleacetic 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.
And one more:
http://www.ncbi.nlm.nih.gov/pubmed/8749023Psychostimulant-like effects of p-fluoroamphetamine in the rat.
Marona-Lewicka D, Rhee GS, Sprague JE, Nichols DE.
Departments of Pharmacology and Toxicology, and Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, IN 47907, USA.
The present study was undertaken to compare the pharmacological properties of p-fluoroamphetamine with those of amphetamine and of other halogenated amphetamines, using several in vivo and in vitro tests. These included substitution testing in (+)-amphetamine (1 mg/kg, 5.4 mu mol/kg, i.p.)-, (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine [(+)-MBDB] (1.75 mg/kg, 7.8 mu mol/kg, i.p.)-, and 5-methoxy-6-methyl-2-aminoindan (MMAI) (1.71 mg/kg, 8 mu mol/kg, i.p.)-trained rats, [3H]5-HT and [3H]dopamine uptake inhibition in whole brain synaptosomes, and changes in striatal extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) as measured by in vivo microdialysis in freely moving rats. In drug discrimination substitution tests, p-fluoroamphetamine fully mimicked (+)-amphetamine (ED50 0.43 mg/kg, 2.11 mu mol/kg), whereas 'no substitution' was observed in rats trained to discriminate the serotonin (5-hydroxytryptamine, 5-HT)-releasing agents (+)-MBDB or MMAI from saline. p-Chloroamphetamine did not substitute for amphetamine but fully substituted for the (+)-MBDB and MMAI cues (ED50 0.17 mg/kg, 0.82 mu mol/kg, and 0.14 mg/kg, 0.69 mu mol/kg, respectively). p-Fluoroamphetamine, in comparison with p-chloroamphetamine and p-iodoamphetamine, showed much stronger inhibition of [3H]dopamine than [3H]5-HT uptake into rat brain synaptosomes but was less selective than amphetamine. p-Fluoroamphetamine (7.0 mg/kg, i.p.), 1 h after administration, strongly elevated (849% of baseline) extracellular dopamine in rat striatum measured using in vivo microdialysis. Amphetamine (2 mg/kg, i.p.) increased extracellular dopamine in rat striatum with a maximum at the same time as did p-fluoroamphetamine, but the latter gave a smaller increase. The data presented suggest that p-fluoroamphetamine resembles amphetamine more than it does the 5-HT-releasing type amphetamines.
I was also under the impression that the flourophenyl group would be excreted unchanged. I was mostly curious as to whether it shared any metabolites with amphetamine, and if you're correct then it doesn't.
Last edited by Coolio; 19-02-2009 at 00:33.
Well, norephedrine is a metabolite of amphetamine. The para-halo group prevents the ring hydroxylation from occurring. I'm guessing on the metabolites based on para-chloroamphetamine metabolism.
I'm not completely sure how correct the conclusion second of the study is. It may just reflect upon 4-Fluoroamphetamine's inability to release serotonin (as stated in the third study).
4-fluoro-norephedrine would never become norephedrine in the human body though right?
I would doubt it, the halogenated rings tend to stay put in the human body. The fluorine bond to the phenyl ring is very strong compared to the other halogens as well.
As mentioned above, the 4-fluoro moiety prevents the formation of a major amphetamine metabolite, 4-hydroxyamphetamine. The other significant metabolites of dextroamphetamine in humans are: benzoic acid and (less so) norephedrine. So, I bet these become 4-fluoro-benzoic acid and 4-fluoro-norephedrine in the case of 4-fluoroamphetamine. Thankfully, the para-fluoro moiety is pretty much inert. I've always wondered what 3,4-difluoroamphetamine would be like--Roman et al (2004) claims that it is a fairly weak inhibitor of [3H]5-HT uptake, supposedly it isn't an MAO-A inhibitor and both 3-fluoro- and 4-fluoro-amphetamine are quite active at the DAT, so it is probably quite a nice compound.
Not discussing the synthesis, but 3,4-difluoroamphetamine should be an easy one to make.
^^No psychoactive drug stays in your body forever--after about 7-8 half-lives, the concentration is effectively no different than zero. There are some highly lipophilic industrial pesticides that can be absorbed into fat cells and remain there for a period of months (at least). Clearly, these are not things that anyone would willingly ingest--as you can imagine, most of them are potent carcinogens.
The longest-lasting psychoactive compounds (in terms of being retained in adipocytes) are the cannabinoids. I think THC has a terminal half-life of 1-7 days (depending upon whether it is acutely or chronically administered), so it can be detectable for up to a month after the last administration.
The idea that LSD remains in your system for decades is nothing but a giant, steaming load of horseshit, as is the idea that LSD can spontaneously cause a full-on psychedelic experience years after dosing.
Thanks Riemann Zeta.
I was referring to the ability of the fluorine to stay attached the aryl ring -- it won't break off at any time inside your body.
does it comes as crystals and does it look the same.
LIke is there any way u can figure out like with meth if its been cut.
what does it look like compared to meth... i know thats vagues cause i seen meth ranging in all colours, tastes, forms and shapes
In its pure form it is a white crystalline powder.
Ring hydroxylation though could happen on different positions than 4?!
Will it make you fail a UA?
My guess is it would come up positive as amphetamine.
Yup, the fluorine binds very strongly to the benzene ring. I mean, fluoxetine (Prozac) has a trifluoromethyl substitution and all the fluoroquinone antibiotics have fluorine substituted rings, I can't imagine is that the fluorine is that dangerous as long as it's bonded to a carbon.
^ the fluoroquinolones are a bad example, the fluorine is known to fall off pretty easily under the influence of light. even so the tox problem is the highly reactive radical rather than the flluoride.
the quantity of fluoride released even if FA did lose the F is pretty miniscule and amounts to eating toothpaste, perhaps people should worry more about ingesting an almost untested CNS active drug, rather than about fluoride.
"perhaps people should worry about ingesting an almost untested CNS active drug"
Especially one such as 4-FA that lacks oomph (yes I have tested it on myself).
But no, the aromatic ring's not about to get hydroxylated anywhere. Aromatic halogens are intrinsically deactivating.
hmmmmmmy friend likes 4FA because of its oooomph.... he used it WAY too much imho... and finally he is slowing down, actually he came to a grinding halt with a kidney stone.... finally he got a warning sign that he registered. I like to think the 4FA (he used it perhaps 2-3 times a week over a prolonnged period of time) may well be something to do with it. Anyone any comment on that?