nomad_scientist said:So does this mean that any drug with the 4-phenyl-4-hydroxypiperidine structure will be metabolised to give dopaminergic neurotoxins? Or would substitution on the piperidine ring stop the metabolite forming the same way. Are there any other well known drugs with this structure in apart from haloperidol and loperamide?
heres my understanding though I haven't found any proper paper that discusses the SAR of tetrahydropyridine type DA neurotoxins: so he are my rules which may be very wrong:
There must be alkyl or substituted alkyl on the 1 position, those substances without alkyl substitution on the nitrogen are not neurotoxins
the 4 hydroxy must be labile, and subject to elimination, so reversed esters are handy
(gets you to the tetrahydropyridine)
AND
the piperidine ring must be either unsusbstituted or substituted in a way that stabilises the next intermediate oxidised form, the dihydropyridine form, 2 double bonds in the pyridine. phenyl on the 4 position is good because of the resonance stabilisation of the dihydropyridine entity. so possibly alkyl at 3 carboxyl at 2 etc will prevent the stabilisation. the reason why I believe the stabilisation to be important is that 4-benzyl-1-methyl tetrahydropyridine is not neurotoxic, the 4 benzyl doesn't stabilse the intermediate dihydropyridine. substitution on the phenyl ring doesn't seem to be important.
similarly moving the phenyl to the 3 position or even the alpha position (2)
abolishes neurotoxicity,
the tetrahydropyridine intermediate needs to have the double bond isolated from the nitrogen and its delocalised resonance stabilising effects.
though I would be careful as rats are MPTP proof.
for example if one was designing a neurotoxin much more potent than MPTP then 4-(3,4-dichlorophenyl) N-methyl- THP would be obvious because it has much higher DAT affinity.
ALSO
I believe neurotoxic isoquinolines exist
and there are definately neurotoxic B-carbolines
a more general comment:
In the interests of harm reduction I would like to point out, there are better avenues for budding home cooking junk chemists to explore.
My advice is do not go there!!!!
there is a general overview of mptp and parkinsons at
http://www.sulzerlab.org/pdf_articles/Fahn_NeuroRX_04.pdf
if I find a SAR for the neurotoxins I'll post it
Last edited: