N&PD Moderators: Skorpio | thegreenhand
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.
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 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.
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.
Ring hydroxylation though could happen on different positions than 4?!