Possible neurotoxicity of 3,4-CTMP

[Transform]

Anyone care to speculate about the possibility for CTMP to be dangerously hydroxlyated? I expect the ester will be easily hydroylsed but anecdotal reports suggest a long active half life, so dichloro ritalinic acid must be active too. Could this be dangerous?

Dichloroamphetamine < < < < > > > > 3,4-CTMP​

Now read this from the Rhodium archive, and bear with me, it won't all be technical jibber jabber and you may want to hear my actual argument:

An unusual aspect of 4-CA metabolism is the reported conversion of the drug to oxygen-containing products. A phenolic product was identified by Parli and Schmidt (1975) as being 3-chloro-4-hydroxyphenylisopropylamine. This would seem to invoke the NIH shift as an explanation for the migration of the chloro atom. Even more remarkable is the report (Sherman and Gal, 1976) of the isolation of 3,4-dimethoxyphenylisopropylamine following the intraventricular injection of 4-CA. This represents the formation in vivo of a weak but accepted pressor and psychotomimetic. When the mechanism of its formation is understood, a chemical link may be at hand tying the simpler phenylisopropylamine stimulants to the methoxylated psychotomimetics. There were no reports from the clinical studies of 4-CA that suggested any psychotomimetic action.

This suggests that given enough room, some hydroxylase apparently oxidizes the halogenated position transfering the Cl to the adjacent position on the phenyl (called NIH shift as mentioned).
In such a compound as DOC or 2C-C there may be too much steric hindrance or the different electronic distribution making it too hard for such an enzyme to gobble on the Chloro.
However if 3,4-dichloroamphetamine also shows toxicity we may want to suspect something similar happening since the 4-chloro can still be relocated to the 5-position and/or the 3-chloro to the 2-position.

I must admit I was skeptic at first of polymath concerns, focussing on the various structural differences rather than the commonalities, but I think the above suggests that we should avoid a compound like this because of the likelihood of shady metabolites by hydroxylase.
Because you really don't want phenolic metabolites, I seem to recall F&B also avoiding anything that might lead to that like the plague and rightly so.

Also I think one of the most similar compounds to this CTMP is dichloropane, I am surprised no one has mentioned it and am also curious if that compound was tested for Raphe nuclei dopaminergic toxicity and things like that.

Then there is also AH-7921 with the same dichlorophenyl pattern but that might be too far from dopaminergic to be relevant. Still if you are a user of that or considering it, this could deter you.

Anyway I saw this drug (CTMP) being offered and after having the thoughts I just expressed decided that it would almost be hubristic to proceed trying it. (Apart from the fact that stimulants have pretty much disappeared from my diet)

If I haven't made myself very clear, ask.

 

[sekio]

If 4-chloroamphetamine is hydroxylated in the liver at the 3' position, why would dichloro compounds also be hydroxylated, when that same position is masked by a humongous chlorine atoms? The human liver is not very good at removing halogens off aromatic rings.

Because you really don't want phenolic metabolites, I seem to recall F&B also avoiding anything that might lead to that like the plague and rightly so.

Amphetamine manages to be turned into 4-hydroxyamphetamine in most opeople without ill effects, why would it "cause the plague"?

 

[Transform]

I think the concern is the "NIH shift" moving things around - I think the whole problem here is that we don't understand the neurotoxicity mechanism of 4-CA, so trying to extrapolate a metabolite profile for CTMP from that is going to prove very challenging.

 

[Solipsis]

Regarding both your posts, it must have been this:

It is used as a neurotoxin by neurobiologists to selectively kill serotonergic neurons for research purposes, in the same way that 6-hydroxydopamine is used to kill dopaminergic neurons.

Must have interpreted the 6-hydroxydopamine thing more like being something equal rather than something similar.

 

[N0 W4RN1NG]

3,4 CTMP is not neurotoxic (at least in the haloamphetamine sense) for several reasons.

As others have already stated, the additional halogen at the 3 position on the benzene ring alters metabolites produced.

As Mela touched on, the haloamphetamines tend to do damage of a serotonergic nature, which seems to require simultaneous reversal of SERT (5HT release) and some degree of stimulation at the 5HT2A receptor. While 3,4 CTMP may have some minor serotonergic properties, I'd bet my left nut that it isn't an agonist at 5HT receptors, and that any increase in intra-synaptical 5HT levels would be attributed to reuptake rather than release.

In addition, (and this has been widely debated on BL for some reason but I'll bring it up again) 4-MMA and MDMA's cathinone counterparts, Mephedrone and Methylone, have been proven to be distinctly lack the serotonergic toxicity of their amphetamine parents. This has been attributed to the beta-ketone interfering with VMAT2 binding, therefore impairing full-fledged 5HT release. Thus, at least for serotonin, Cathinone-type drugs tend to generally only be capable of inhibiting the reuptake of said neurotransmitter.

Using this logic, it was postulated that 4-BMC, the analogue of the HIGHLY neurotoxic drug 4-BMA, would actually be relatively safe, despite it's scary resemblance. While I have seen no formal studies confirming this (or disproving it) it seems that 4-BMC is widely used all over the world and has no difference in side effects to any of the other more popular cathinone stimulants.

Subjectively at least, this alludes to a confirmation of this ketone-induced inability to cause violent 5HT destruction.

Where am I going with all this? Well - 3,4 CTMP, like MPH, has a beta-methylacetate group, structurally a lot closer to the cathinones' beta-ketone moiety and could be expected to prevent activation of the VMAT2 receptor in a similar fashion.

TL;DR: For the above reasons, I don't believe ANY halogenic substitution on methylphenidate's benzene ring could yield 5HT neurotoxicity reminiscent of the haloamphetamines.

3,4 CTMP is almost certainly a safe compound. Whether or not it's actually enjoyable, however, is probably a different matter.

 

[specialspack]

In addition, (and this has been widely debated on BL for some reason but I'll bring it up again) 4-MMA and MDMA's cathinone counterparts, Mephedrone and Methylone, have been proven to be distinctly lack the serotonergic toxicity of their amphetamine parents. This has been attributed to the beta-ketone interfering with VMAT2 binding, therefore impairing full-fledged 5HT release. Thus, at least for serotonin, Cathinone-type drugs tend to generally only be capable of inhibiting the reuptake of said neurotransmitter.

Using this logic, it was postulated that 4-BMC, the analogue of the HIGHLY neurotoxic drug 4-BMA, would actually be relatively safe, despite it's scary resemblance. While I have seen no formal studies confirming this (or disproving it) it seems that 4-BMC is widely used all over the world and has no difference in side effects to any of the other more popular cathinone stimulants.

Subjectively at least, this alludes to a confirmation of this ketone-induced inability to cause violent 5HT destruction.
.

Is there a thread/refs to all of this, please?

 

[N0 W4RN1NG]

Is there a thread/refs to all of this, please?

Yup

 

[specialspack]

In addition, (and this has been widely debated on BL for some reason but I'll bring it up again) 4-MMA and MDMA's cathinone counterparts, Mephedrone and Methylone, have been proven to be distinctly lack the serotonergic toxicity of their amphetamine parents. This has been attributed to the beta-ketone interfering with VMAT2 binding, therefore impairing full-fledged 5HT release. Thus, at least for serotonin, Cathinone-type drugs tend to generally only be capable of inhibiting the reuptake of said neurotransmitter.

Hang on... the paper in question (Baumann et al 2012) shows 4-MMC induced an increase to over 950% of baseline extracellular concentration of 5HT, whereas MDMA induced an increase of around 750%. They state specifically that mephedrone and methylone are releasers rather than re-uptake inhibitors:

"More specifically, the drugs evoke transporter-mediated release of monoamines via reversal of normal transporter flux... Using assay methods, which can discriminate releasers from uptake blockers, we demonstrate here that a fundamental mechanism of action for mephedrone and methylone is substrate activity at monoamine transporters." (p.1200)

So their apparent lack of neurotoxicity isn't predicated on them not being releasers, although it might be to do with their lower potency at VMAT2. And I wouldn't want to say at this stage it was proven that they're non neurotoxic, given the limited number of studies so far.

 

[specialspack]

However, proven isn't really a term that should be used even after 1/10/100/1000 studies. Leave that term for the mathematicians and theologians. But the current weight of evidence would suggest not neurotoxic (from the typical 5-HT angle). And like all scientific conclusions: tentative, with a dollop of uncertainty. Just like it should be.

Yes yes, I'm familiar with the arguments on deduction, inference, falsificationism, inference to the best explanation etc. in the context of the scientific method.

Although off-topic, the lack of neurotoxicity of mephedrone is very interesting. I suppose there's another thread on that somewhere...