I Like to Draw Pictures of Random Molecules

[DotChem]

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.

.......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......

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! 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..

..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.

why is inhibition of AAAH more neurotoxic to 5HT

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 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

 

[DotChem]

but 6-CAT is non-neurotoxic according to Pr Dave Nichols:

wiki: 6-CAT

6-Chloro-2-aminotetralin (6-CAT) is a drug which acts as a selective serotonin releasing agent (SSRA) and is a putative entactogen in humans.^[1][2] It is a rigid analogue of para-chloroamphetamine (PCA).^[1]

According to Nichols et al.,^[3] 6-CAT is a non-neurotoxic analog of PCA.

 

[Nagelfar]

here is one ref for TPH: http://www.ncbi.nlm.nih.gov/pubmed/8015380 (you can find lots of refs for other AAHs.

Added info to WP, thanks for that one Do(t)C.

 

[aced126]

QUOTE=aced126;13480853]Interesting hypothesis. Do you have a source for this?

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! 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.



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 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

Where can I find more about the mechanism? Wikipedia has nada.

 

[DotChem]

Exact same thing for phenylalanine => tyrosine and tyrosine => l-DOPA (the heterocylcle on top is the biopterin co-factor.
Mechanisms of tryptophan and tyrosine hydroxylase http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270200/

The aromatic amino acid hydroxylases tryptophan hydroxylase and tyrosine hydroxylase are responsible for the initial steps in the formation of serotonin and the catecholamine neurotransmitters, respectively. Both enzymes are nonheme iron-dependent monooxygenases that catalyze the insertion of one atom of molecular oxygen onto the aromatic ring of their amino acid substrates, using a tetrahydropterin as a two electron donor to reduce the second oxygen atom to water. This review discusses the current understanding of the catalytic mechanism of these two enzymes. The reaction occurs as two sequential half reactions: a reaction between the active site iron, oxygen, and the tetrahydropterin to form a reactive Fe^IVO intermediate and hydroxylation of the amino acid by the Fe^IVO. The mechanism of formation of the Fe^IVO is unclear; however, considerable evidence suggests the formation of an Fe^II-peroxypterin intermediate. The amino acid is hydroxylated by the Fe^IVO intermediate in an electrophilic aromatic

(the full review paper is free! and very up to date) .. good luck

 

[DotChem]

more details (from same paper)....

 

[Incunabula]

I know we don't do synth talk here, but how difficult would it theoretically be to remove the acetic acid from the β carbon? And am I correct in thinking, that it would be a substitution reaction?

Edit: I guess it's a decarboxylation. How difficult and dangerous is it. (theoretically, I'm not about to blow myself up just yet)

 

[Nagelfar]

Altinicline + Fenclonine

(for some reason, no clue why, just random association inspired me)

 

[roi]

 

[Dresden]

but 6-CAT is non-neurotoxic according to Pr Dave Nichols:

wiki: 6-CAT

I wouldn't touch that with a ten foot pole.

 

[Solipsis]

Yea 2-aminotetralin itself appears dangerous and nasty in humans from anecdotes (secondhand from nuke), so it's not even the pCA analogy alone warranting that wide berth..

I really like the phenidates vs modafinils hybrid / analogues - tickling structures roi

 

[DotChem]

any idea why the tetralines so nasty.. not very different from simple PEA at first glance!

 

[DotChem]

talking about tetralines...Dissociatives Stims

 

[Solipsis]

Not bad, in morphinans including DXM there is the same 2-aminotetralin configuration. In that tetraphenidine the phenyl is perhaps not necessarily as optimal for PCP-site binding as the phenyl in PCP itself, because the one side of the aromatic ring in the tetralin would fulfill that role mimicking the carbonyl function of glutamate. Demonstrated by DXO's structure I guess.
For mimicking glycine there is one less spacer... I wonder if you can make the drug more selective that way. It might mean that diphenidine type structures are dirty that way overlaying with glutamate and glycine?

Might not be such a bad idea to simplify and modify DXO to make it optimal as a recreational drug (as opposed to a metabolite of cough suppressant medication), in a similar way as MXE was an ingenous design starting from ketamine as the ACH template.

Log p yeah not to ignore, but I'm not sure if slapping phenyls on drugs is such a great idea if they don't actively play a role in binding... The stupidly long durations of many popular dissociatives are to me one of the banes.
Instead add some polar groups that besides facilitating excretion improve on the drug's effects, like perhaps borrowing the idea from -OH on DXO to make a 6-tetralinol.

 

[DotChem]

..in morphinans including DXM there is the same 2-aminotetralin configuration...

You're right! actually that may explain problems with tetralines!! If they get para-hydroxylated in first pass metabolism (a real possibility),then you might end up with a potentially potent morphinan like structure with the 6-phenolic OH in the right position ala DXM. At least for the unsubstituted ones. So stims/nmda doses would certainly correspond to mortal opioid ods. If that is the case though, then the 6-chloro-2-amino tetralines may also be toxic in that sense; not necessarily neurotoxic...

On the other hand, 2-amino-indanes seems to be ok...(not sure about the corresponding 6-chloro-2-aminoindane!)

In that tetraphenidine the phenyl is perhaps not necessarily as optimal for PCP-site binding as the phenyl in PCP itself, because the one side of the aromatic ring in the tetralin would fulfill that role mimicking the carbonyl function of glutamate..

Very true! the question is how much can the cyclohexyl (the PCP cyclohexyl) binding site accomodate? I guess one can tinker around with this part of PCP and still retain some Glu-site activity but yeah, tetraline seems too big. cf benocyclidine where the Ph of PCP is replaced by 2-thiophenyl gives 0 NMDA activity but potent and pure DRI with no SERT or NET!!

For mimicking glycine there is one less spacer... I wonder if you can make the drug more selective that way. It might mean that diphenidine type structures are dirty that way overlaying with glutamate and glycine?

may be an aminoindane like this?

But they're harder to synthesize..(almost always catalytic hydrogenation step! I always hated Parr hydrogenators lest you're trying to bl0w the lab up!)

Might not be such a bad idea to simplify and modify DXO to make it optimal as a recreational drug (as opposed to a metabolite of cough suppressant medication), in a similar way as MXE was an ingenous design starting from ketamine as the ACH template.

Can't diphenidine really be looked at as a simplified version of DXO with the 1-phenyl mimicking the cyclohexyl of DXO? like this:

Log p yeah not to ignore,

logP are pretty decent. a bit on the lipophilic side but not very different from diphenidine(1.5-1.8 @pH7.4).

but I'm not sure if slapping phenyls on drugs is such a great idea if they don't actively play a role in binding... The stupidly long durations of many popular dissociatives are to me one of the banes.
Instead add some polar groups that besides facilitating excretion improve on the drug's effects,

Now that's serious PK issues you raised: ridiculously long half-life of hydrophobic molecules.

How about Ph ----> CO2Et replacement? which bring me back to some structures related to methylphenidate I suggested earlier. will the CO2ET mimick the CO2H of Glu at NMDAr site?!

or

extremely easy synthesis .. half life probably similar to MPH (the ester.. the ketone a little longer!). potential dissociatives stim?

like perhaps borrowing the idea from -OH on DXO to make a 6-tetralinol.

Caution though with 6-hydroxy tetralines: lest you end up with morphinan-like opiods. But with a little luck the piperidine ring (instead of simpler amino) might make them ANTAGONISTS rather than agonists at opiates receptors if they happen to have any affinity at all for OPs.. but who knows?

 

[aced126]

Aminotetralins aren't toxic in the fact that they cause respiratory arrest. Rather, they reduce the seizure threshold, something which is not caused by opioids.

 

[crmt28]

2C-iP with a "ButterFLY" structure, but on the 4 and 5 positions instead. Pretty interesting molecule, looks kinda like THC!

EDIT:

Oops, Shulgin already did it with the F-x series, with a furan ring instead.
But he didn't seem to try the alpha unmethylated versions.

 

[Nagelfar]

^This reminds me of a methylphenidate methylenedioxy version of cocaine; inasmuch as cocaine has a methyl acetate (to the phenyl, the benzoate) and a carbmethoxy which is basically the inverse of the other: it is much likewise with the cyclopentane methylenedioxies in the above MPH derivative.

 

[Pomzazed]

^
That "1,3-dioxolane" (the five member ring with 2 oxygen) will RAPIDLY hydrolyses in contact with water (catalysed by H+ also, and will be alot faster) into aldehyde group plus ethylene glycol (very toxic to kidney forming oxalate kydney stone rapidly)

I wont touch this molecule also...

 

[aced126]

^
That "1,3-dioxolane" (the five member ring with 2 oxygen) will RAPIDLY hydrolyses in contact with water (catalysed by H+ also, and will be alot faster) into aldehyde group plus ethylene glycol (very toxic to kidney forming oxalate kydney stone rapidly)

I wont touch this molecule also...

Why so? Cyclic acetals are more stable than normal acetals and anyway doesn't acetal hydrolysis occur slowly unless catalysed by H+. By the same argument you could say that methylphenidate will rapidly hydrolyse to ritalinic acid and methanol (which might blind you...not, not at that dose anyway). Ethylene glycol is not toxic in milligram range.