4-acylamphetamines?

[Limpet_Chicken]

Is anything known of the pharmacology, if they are active, of para-acylamphetamines, particularly para-acetylamphetamine?

Are they/is it (4-acetylamphetamine/4-acetylcathinone) active? and if so do they suffer from the nasty effects ascribable to quite a few of the monosubstituted amphetamines where the substituent is on the carbon para to the alkylamine sidechain?

 

[Solipsis]

You mean p-Ac-amph or p-AcO-amph?

Even if extending the para-group makes it less potent, departing from both 4-MA and PMA seem worrisome in that they are unsafe serotonergic releasers although they act a little differently. But clearly you know of those already...

But no nothing comes up on 1-(4-acetylphenyl)propan-2-amine.

 

[Limpet_Chicken]

I mean para-acetyl.

And yes, I know of the often nasty character of para-monosubstituted amphetamines, I was just curious enough to post on a possibility, wasn't one I was about to hare off to the lab and whack some up unless I'd got confirmation of it NOT being something inherently noxious. But of course, no harm in seeking further information.

Can't say I have high hopes about this molecule, but of course it is a pretty unusual divergence from the usual substituents.
Would expect it to be rapidly metabolized, and the unmetabolized drug to be quickly excreted too due to its very polar nature.

I'm far more hopeful for 3-bromo-4-difluoromescaline, 3-bromo-4-difluoro-TMA and 3-bromo-4-difluoromethoxy-5-methoxycathinone.

 

[serotonin2A]

The danger with p-acetyl-AMPH (and also p-acetoxy-AMPH) is that it would be predicted to produce PMA-like effects. Amphetamines with lipophilic substituents in the para position tend to have high affinity for SERT and for MAO-A, which makes them somewhat selective for serotonin release and increases the risk of serotonin syndrome or fatal hyperthermia. Besides PMA, other examples include p-methylthio and p-methyl.

With PMA, my recollection is that part of the problem is due to the metabolite p-hydroxyamphetamine. That explains why people who are CYP rapid metabolizers are more likely to die after ingesting PMA. So p-acetoxyamphetamine would probably be a bad idea.

I mean para-acetyl.

I'm far more hopeful for 3-bromo-4-difluoromescaline, 3-bromo-4-difluoro-TMA and 3-bromo-4-difluoromethoxy-5-methoxycathinone.

This list of compounds is a bit strange. The nomenclature of the first two is impossible. But lets assume you are talking about e.g. 3-Br-4-difluoromethoxy-5-methoxyphenethylamine. That compound doesn't really fit with the known SAR of mescaline derivatives -- assuming that you are looking for activity at 5-HT2A. The 3-methoxy group in mescaline is believed to act as a H-bond acceptor, so replacing it with bromine would likely reduce affinity while also reducing ligand efficiency (ie, the situation where Br does not increase affinity over H but makes the molecule heavier).

 

[Limpet_Chicken]

Yes, I meant the homologs of the compound generally referred to (non-IUPAC) as 'difluoromescaline', I.e where a difluoromethoxy replaces the 4-position methoxy, but see my other thread on those, which I see you have done)

A bit strange in what sense? I was merely mildly curious as to the acyl amphetamines, not something I was particularly enthusiastic about either taking, or making. A theoretical possibility, is all the para-acetylamphetamine represented, little more than that, I'd come to more or less the same conclusion that you had. I.e probably not a good idea.

 

[aced126]

The danger with p-acetyl-AMPH (and also p-acetoxy-AMPH) is that it would be predicted to produce PMA-like effects. Amphetamines with lipophilic substituents in the para position tend to have high affinity for SERT and for MAO-A, which makes them somewhat selective for serotonin release and increases the risk of serotonin syndrome or fatal hyperthermia. Besides PMA, other examples include p-methylthio and p-methyl.

With PMA, my recollection is that part of the problem is due to the metabolite p-hydroxyamphetamine. That explains why people who are CYP rapid metabolizers are more likely to die after ingesting PMA. So p-acetoxyamphetamine would probably be a bad idea.



This list of compounds is a bit strange. The nomenclature of the first two is impossible. But lets assume you are talking about e.g. 3-Br-4-difluoromethoxy-5-methoxyphenethylamine. That compound doesn't really fit with the known SAR of mescaline derivatives -- assuming that you are looking for activity at 5-HT2A. The 3-methoxy group in mescaline is believed to act as a H-bond acceptor, so replacing it with bromine would likely reduce affinity while also reducing ligand efficiency (ie, the situation where Br does not increase affinity over H but makes the molecule heavier).

What is the hyperthermia specficially mediated by?

What is it that makes stuff like PMA and MTA more dangerous than say MDMA itself?

What makes p-OH-amphetamine more lethal than say PMA?

 

[Solipsis]

Malignant hyperthermia is apparently hypothesized to be mediated by an imbalance between dopaminergic and serotonergic function in the hypothalamus. Possibly the fact that some of these 4-substituted amphetamines have relative selectivity for serotonergic release or even more reuptake inhibition could lead to such an imbalance more quickly than MDMA which has triple monoaminergic activity.

So perhaps next time someone is threatened by drug-induced hyperthermia from such a selective serotonergic drug he needs to snort some methylphenidate? Yeah, or perhaps not.

p-OH-amphetamine more lethal than PMA? Really? It's a metabolite of amphetamine... seems like either that claim is not correct or not very much is produced. The p-OH is supposed to have MAOI activity but even if it is solely responsible for most of amphetamines MAOI activity that isn't all that potent, hence my rationale.

 

[aced126]

Also another question I have been pondering for a while.

Is the density of SERT expression uniform across all synapses and brain regions (I'm guessing very likely not, just as receptor and receptor subtypes are distributed very unevenly)? If this is the case surely drugs like MDMA are increasing serotonergic function in different areas of the brain that would give a wildly different behavioural response compared to hypothetically injecting serotonin in all parts of the brain. So maybe could this give us clues as to where SERT is expressed more in serotonergic synapses (e.g. amygdala)?

 

[serotonin2A]

Yes, I meant the homologs of the compound generally referred to (non-IUPAC) as 'difluoromescaline', I.e where a difluoromethoxy replaces the 4-position methoxy, but see my other thread on those, which I see you have done)

A bit strange in what sense? I was merely mildly curious as to the acyl amphetamines, not something I was particularly enthusiastic about either taking, or making. A theoretical possibility, is all the para-acetylamphetamine represented, little more than that, I'd come to more or less the same conclusion that you had. I.e probably not a good idea.

You cant add a substituent to C3, C4, or C5 in mescaline without removing the methoxy groups that are already in those positions. For example 3-methylmescaline would mean 3-methyl-3,4,5-trimethoxyphenethylamine, which is impossible.

Malignant hyperthermia is apparently hypothesized to be mediated by an imbalance between dopaminergic and serotonergic function in the hypothalamus. Possibly the fact that some of these 4-substituted amphetamines have relative selectivity for serotonergic release or even more reuptake inhibition could lead to such an imbalance more quickly than MDMA which has triple monoaminergic activity.

So perhaps next time someone is threatened by drug-induced hyperthermia from such a selective serotonergic drug he needs to snort some methylphenidate? Yeah, or perhaps not.

p-OH-amphetamine more lethal than PMA? Really? It's a metabolite of amphetamine... seems like either that claim is not correct or not very much is produced. The p-OH is supposed to have MAOI activity but even if it is solely responsible for most of amphetamines MAOI activity that isn't all that potent, hence my rationale.

You have to remember that p-hydroxylation is not the only metabolic route for AMPH, whereas p-OH-AMPH is the primary metabolite of PMA. Then also keep in mind that acute doses of PMA are much higher than acute doses of AMPH, meaning that someone who takes PMA is going to be exposed to more p-OH-AMPH then someone who takes AMPH.

However, I think an even bigger problem with PMA is that it is demethylated by CYP in the brain, whereas AMPH is p-hydroxylated mostly in the periphery. That means that there isn't much CNS exposure to p-OH-AMPH after use of AMPH.

 

[Cotcha Yankinov]

Also another question I have been pondering for a while.

Is the density of SERT expression uniform across all synapses and brain regions (I'm guessing very likely not, just as receptor and receptor subtypes are distributed very unevenly)?

I've wondered about this myself in regards to differential response to SSRIs and the serotonin portion of MAOIs .

It appears that the expression of SERT is not just dependent on brain location but the time of development as well http://www.ncbi.nlm.nih.gov/m/pubmed/27282696/

http://www.ncbi.nlm.nih.gov/m/pubmed/24904298/

https://www.ncbi.nlm.nih.gov/core/l...om&p=PMC3&id=4032978_fncir-08-00052-g0003.jpg

^Helpppppp S2A, is that slice showing increased SERT expression more towards the cortex?

There are also apparently neurons that absorb 5-HT through SERTs but they do not synthesize any themselves https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153855/#!po=0.920245

"Serotonin absorbing neurons use serotonin reuptake transporter to uptake serotonin from extracellular space but do not synthesize it.

Loss of mod-5/SERT function blocks the 5-HT absorption. mod-5/SERT mutants have been shown to exhibit exaggerated locomotor response to food deprivation. We found that transgenic expression of MOD-5/SERT in the 5-HT-absorbing neurons fully corrected the exaggerated behavior. Experiments of cell-specific inhibition of synaptic transmission suggest that the synaptic release of 5-HT from the 5-HT-absorbing neurons is not required for this behavioral modulation. Our data point to the role of 5-HT-absorbing neurons as temporal-spatial regulators of extrasynaptic 5-HT.

Regulation of extrasynaptic 5-HT levels by 5-HT-absorbing neurons may represent a fundamental mechanism of 5-HT homeostasis, integrating the activity of 5-HT-producing neurons with distant targets in the neural circuits, and could be relevant to some actions of SSRIs in human."

What the hell 0.0 Also sorry to derail thread.

 

[Solipsis]

You cant add a substituent to C3, C4, or C5 in mescaline without removing the methoxy groups that are already in those positions. For example 3-methylmescaline would mean 3-methyl-3,4,5-trimethoxyphenethylamine, which is impossible.


You have to remember that p-hydroxylation is not the only metabolic route for AMPH, whereas p-OH-AMPH is the primary metabolite of PMA. Then also keep in mind that acute doses of PMA are much higher than acute doses of AMPH, meaning that someone who takes PMA is going to be exposed to more p-OH-AMPH then someone who takes AMPH.

However, I think an even bigger problem with PMA is that it is demethylated by CYP in the brain, whereas AMPH is p-hydroxylated mostly in the periphery. That means that there isn't much CNS exposure to p-OH-AMPH after use of AMPH.

Didn't know CYP p450 2D6 did all that in the CNS as well, very educative... So since expression of that enzyme is a bit localized you can expect formation of p-OH-amph to be localized in the brain as well?
And that's a good explanation for p-OH amph.

 

[serotonin2A]

I've wondered about this myself in regards to differential response to SSRIs and the serotonin portion of MAOIs .

It appears that the expression of SERT is not just dependent on brain location but the time of development as well http://www.ncbi.nlm.nih.gov/m/pubmed/27282696/

http://www.ncbi.nlm.nih.gov/m/pubmed/24904298/

https://www.ncbi.nlm.nih.gov/core/l...om&p=PMC3&id=4032978_fncir-08-00052-g0003.jpg

^Helpppppp S2A, is that slice showing increased SERT expression more towards the cortex?

There are also apparently neurons that absorb 5-HT through SERTs but they do not synthesize any themselves https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153855/#!po=0.920245

"Serotonin absorbing neurons use serotonin reuptake transporter to uptake serotonin from extracellular space but do not synthesize it.

Loss of mod-5/SERT function blocks the 5-HT absorption. mod-5/SERT mutants have been shown to exhibit exaggerated locomotor response to food deprivation. We found that transgenic expression of MOD-5/SERT in the 5-HT-absorbing neurons fully corrected the exaggerated behavior. Experiments of cell-specific inhibition of synaptic transmission suggest that the synaptic release of 5-HT from the 5-HT-absorbing neurons is not required for this behavioral modulation. Our data point to the role of 5-HT-absorbing neurons as temporal-spatial regulators of extrasynaptic 5-HT.

Regulation of extrasynaptic 5-HT levels by 5-HT-absorbing neurons may represent a fundamental mechanism of 5-HT homeostasis, integrating the activity of 5-HT-producing neurons with distant targets in the neural circuits, and could be relevant to some actions of SSRIs in human."

What the hell 0.0 Also sorry to derail thread.

SERT expression is for the most part proportional to the density of serotonergic innervation. However, there is a subclass of serotonergic projections from median raphe nucleus to do not express SERT, which allows the projections to signal via volume transmission (ie, extrasynaptic transmission).

I didn't see the figure captions from the jpg you asked about, but the top row of images were taken from cortical slices (V1 and V2 are primary and secondary visual cortices).

For the most part, the nonserotonergic neurons that express SERT represent a developmental stage and are not seen in the adult brain.

 

[Cotcha Yankinov]

Whoopsies! I see now there is no caption, my apologies - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032978/figure/F3/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032978/figure/F10/ - Okay so for example image K of the SERTs in Amygdala apparently shows very dense SERT expression around the borders. I'm seeing dense SERT expression around the borders of the structure in question in the other slides as well.

Assuming this isn't a histological artifact, could the purpose of the dense SERT expression around the border of brain structures be to clean up serotonin and stop it from diffusing across into another brain region, essentially the SERTs could be acting like a border and reducing noisy volume transmission?

Or is it just simply that there is denser serotonin innervation around the borders of structures and that coincides with denser SERT expression? Because if the increased SERT expression around borders of structures is indeed acting like a border, then reversal of SERTs must wreak havoc on the segregation of volume transmission...

SERTs build a wall, make the brain great again 8(

 

[serotonin2A]

Assuming this isn't a histological artifact, could the purpose of the dense SERT expression around the border of brain structures be to clean up serotonin and stop it from diffusing across into another brain region, essentially the SERTs could be acting like a border and reducing noisy volume transmission?

Volume transmission is by definition unsegregated. There are high levels of SERT expression because the region receives dense serotonergic input.