QUOTE=aced126;13480853]Interesting hypothesis. Do you have a source for this?[/QUOTE]
paraChloroPhenylalanine is a known irreversible inhibitor of AAAH especially TrypHydroxylase.
here is one ref for TPH: http://www.ncbi.nlm.nih.gov/pubmed/8015380 (you can find lots of refs for other AAHs.
! but replace the CO2H of PCPA by a methyl and you get PCA.
I dont see why they souldn't act similarly to PCPA ie inhibitor of AAAH (may be less efficiently but still enough to fry some serotonergic neurons!). Am not sure if anybody has specically study neurotoxicities of PCA but if you dig a bit, am sure you'll find papers on that..
Not quite! it is a bit more complicated: AAAH enzymes used Fe and a cofactor(biopterin) and the mechanism is radical (not nucleophilic attack..etc). the enzyme grab the para H (in the form of free radical) and replace it with OH via a radical H tranfer mechanism with the help of iron Fe and cofactor (too complicated to elaborate here on PD but important thing is: apparently the enzyme generates DEADLY chloro or bromo free radicals that then kill itself) Much more complicated than that but you get the idea.
paraChloroPhenylalanine is a known irreversible inhibitor of AAAH especially TrypHydroxylase.
here is one ref for TPH: http://www.ncbi.nlm.nih.gov/pubmed/8015380 (you can find lots of refs for other AAHs.
Now to my knowledge much less serious studies have been done on ParachloroAmphetamine: the US gov wont give you research $$ to make better stims for the sake of getting wired.......PCPA is a potent, specific and irreversible inhibitor of TPH activity which drastically reduces 5-HT concentration in the 5-HT neurons and terminals. When PCPA was administered, TPH activity in both cell bodies and nerve terminal areas, was reduced to 10% of control values and recovered to the control levels by day 7 in raphe nucleus, and within 14 days in the hypothalamus. In serotonergic terminal areas, 5-HT could not be detected immunohistochemically at day 1, but slowly recovered within 2 weeks......



I dont see why they souldn't act similarly to PCPA ie inhibitor of AAAH (may be less efficiently but still enough to fry some serotonergic neurons!). Am not sure if anybody has specically study neurotoxicities of PCA but if you dig a bit, am sure you'll find papers on that..
..but how can they irreversibly inhibit the enzyme? The only possible thing that could happen is a nucleophilic residue attacking the aromatic carbon and the halogen leaves; unlikely seeing as there are no EWGs to stabilise the intermediate. Maybe there are downstream cellular changes which cause irreversible inhibition.
Not quite! it is a bit more complicated: AAAH enzymes used Fe and a cofactor(biopterin) and the mechanism is radical (not nucleophilic attack..etc). the enzyme grab the para H (in the form of free radical) and replace it with OH via a radical H tranfer mechanism with the help of iron Fe and cofactor (too complicated to elaborate here on PD but important thing is: apparently the enzyme generates DEADLY chloro or bromo free radicals that then kill itself) Much more complicated than that but you get the idea.
I don;t know. It could be probably as simple as distribution of the molecules ie if it tends to accumulate preferably in 5HT rich brain regions. Another reason may be depletion of 5HT by irreversibly blocking TPH lead to cells death.. but who knows?why is inhibition of AAAH more neurotoxic to 5HT
why are 3-haloamphetamines less selective for 5HT neurons? </QUOTE>
?? in terms of what? if anything 3-halo should not have similar neurotoxicity while beeing as potent as the 4-halo (see bupropion )
more ...later