Is it known how different substitutions of 2c-x affect different parts of the brain?

[Pindar]

And I ask this, because I've tried both 2c-e and 2c-p...the latter to a point to which some might call excessive. The only difference in chemical structure between them is that one has an ethyl chain in the 4th position while the other has a pentyl chain. However the latter made it difficult to speak, had no major open-eyed visuals (at least in the 20mg dose I took), except for the occasional trails and fluctuations, the closed-eyed being geometric shapes...it was more of a mental stimulation...strictly of philosophical subjects and whatnot; while the former was a different beast indeed (the least i can say of it was it didn't make my tongue heavy lol)

 

[immad]

AFAIK not, that's why they're called research chemicals. Btw, 2C-P has a propyl chain (3C) at the fourth position, not pentyl (5C).

 

[sekio]

What do you mean by 'affect different parts of the brain'? The receptor affinities and pharmacokinetics have been worked out pretty well, if that's what you're asking about. The 2c- series act as broad spectrum serotonin agonists with an additional adrenergic component.

 

[Astavats]

Aside that, from my understanding a single site can give unique responses with different drugs activating it (see functional selectivity).

 

[nirvus]

Yes Astavats, that is my understanding as well. i just finished a chemistry degree and did research this summer on the action of hallucinogenic drugs. The main hallucinogenic response to the 2c-x series chems is almost certainly mediated by the serotonin type 2a receptor (5ht2a). that being said, their are at least two ways that 2ce and 2cp can elicit different effects. the main effects are mediated by 5ht2a but as sekio pointed out, they are by no means selective. they bind to many serotonin receptors and also adrenergic receptors and since they may have different binding affinities and intrinsic activities at each receptor subtype, that's a lot of variability when taken all together.
also, and this i found out about during my research, 5ht2a receptor is very flexible when it comes to what drugs it will bind in what configurations and what responses it can have. for instance, it even has a separate dopamine binding site, with discrete signal path. and not all strong agonists are hallucinogenic. it is certainly not an "all or nothing" kind of receptor. so even at just this one receptor, there is a lot of room for there to be variability between closely related analogs.

been a big fan of ethyl analog for years, never had the propyl. sorry if this was wordy, i'm a nerd. also i'm trying to get un-green so i can post the images i rendered this summer of hallucinogens docked into my working model of the 5ht2a receptor. they are beautiful. anyone interested?

 

[I NUK3D U]

Yes Astavats, that is my understanding as well. i just finished a chemistry degree and did research this summer on the action of hallucinogenic drugs. The main hallucinogenic response to the 2c-x series chems is almost certainly mediated by the serotonin type 2a receptor (5ht2a). that being said, their are at least two ways that 2ce and 2cp can elicit different effects. the main effects are mediated by 5ht2a but as sekio pointed out, they are by no means selective. they bind to many serotonin receptors and also adrenergic receptors and since they may have different binding affinities and intrinsic activities at each receptor subtype, that's a lot of variability when taken all together.
also, and this i found out about during my research, 5ht2a receptor is very flexible when it comes to what drugs it will bind in what configurations and what responses it can have. for instance, it even has a separate dopamine binding site, with discrete signal path. and not all strong agonists are hallucinogenic. it is certainly not an "all or nothing" kind of receptor. so even at just this one receptor, there is a lot of room for there to be variability between closely related analogs.

been a big fan of ethyl analog for years, never had the propyl. sorry if this was wordy, i'm a nerd. also i'm trying to get un-green so i can post the images i rendered this summer of hallucinogens docked into my working model of the 5ht2a receptor. they are beautiful. anyone interested?

Very much so.

Could you also expand on this or provide a decent resource link? -

it even has a separate dopamine binding site, with discrete signal path

 

[Astavats]

Sounds interesting, I second on both fronts.

 

[/navarone/]

Read this fantabulous thread by our late member FastandBulbous:

http://www.bluelight.ru/vb/threads/167978-Acid-dragonflies-and-the-5HT2A-receptor?highlight=receptor

Pictures (which where the most explanatory) unfortunately removed, prob to expired webhosting.

Great read.

 

[/navarone/]

Also Shulgin discovered that 2-CB (by means of radioactive bromine radio-imaging) found out that the substance accumulated in the lungs before reaching the brain suggesting that the lungs metabolize 2-CB into a different compound before reacing hte CNS.

 

[nirvus]

S. Bhattacharyya, I. Raote, A. Bhattacharya, R. Miledi and
M. M. Panicker, Proc. Natl. Acad. Sci. U. S. A., 2006, 103,
15428–15253.

I have not read this article but it is referred to here

It has also
been shown that dopamine, considered a separate neurotransmitter
with its own set of cognate GPCRs, can interact
with and activate the receptor initiating other effector pathways
than the normal ones carried out by serotonin.16

in this article which i have:
Molecular modeling and docking studies of human 5-hydroxytryptamine
2A (5-HT2A) receptor for the identification of hotspots for ligand
binding
www.rsc.org/molecularbiosystems | Molecular BioSystems
Karuppiah Kanagarajadurai,y Manoharan Malini,y Aditi Bhattacharya,
Mitradas M. Panicker and Ramanathan Sowdhamini*
Received 31st March 2009, Accepted 12th August 2009
First published as an Advance Article on the web 8th September 2009
DOI: 10.1039/b906391a

 

[nirvus]

thx for link navalone. having some internet troubles atm so it'll be a day or two before i can really get busy and post some fab images of 2c-x molecules hard at work. i'm kinda new to posting.

 

[Astavats]

Thank you for the articles. Bonus that the latter paper discusses 5-HT2A antagonist docking as well.

 

[nirvus]

Bonus that the latter paper discusses 5-HT2A antagonist docking as well.

Glad you can find that paper. I basically reproduced that whole experiment independently this summer. started with sequence homology analysis, generated 3D model from predicted folding of amino acid sequence (but using new tools not available in 2008 ), i even bound the same 8 ligands they did and got nearly identical binding modes and binding energies. so of course i went on to dock and image more exotic 5ht2a agonists ; )

is there any way to post pics b4 i get to 50 posts? lol

 

[Astavats]

You could try photobucket.com, imageshack.us, tinypic.com or other image hosting sites.

 

[Enkidu]

for instance, it even has a separate dopamine binding site, with discrete signal path.

S. Bhattacharyya, I. Raote, A. Bhattacharya, R. Miledi and
M. M. Panicker, Proc. Natl. Acad. Sci. U. S. A., 2006, 103,
15428–15253. wrong citation

It has also
been shown that dopamine, considered a separate neurotransmitter
with its own set of cognate GPCRs, can interact
with and activate the receptor initiating other effector pathways
than the normal ones carried out by serotonin.16

Edit: the correct citation is PNAS October 10, 2006 vol. 103 no. 41 15248-15253. It is available online for free.

I know that 7TMRs can dimerize, and I'd imagine that dimerization with dopamine receptors explains how dopamine exerts influence over the signaling of the 5-HT2A receptor. Of course, there could be some direct interaction, and if there is the 5-HT2A probably has a very low affinity for dopamine. Another possibility is splice variants, but I'd have to see the full article..

Paraphrase: Could 2C-P and 2C-E affect separate parts of the brain differently?

It is possible. Receptor populations differ in expression (concentration) in various brain regions, aka tissues. Finding out the concentrations of coupling proteins in different tissues is also important in understanding the stoichiometry of the protein - protein interactions. So, slightly different agonist directed trafficking combined with different protein expression can lead to quite different physiological responses. However, in this case, I'd have to wonder about off target interactions.

Also Shulgin discovered that 2-CB (by means of radioactive bromine radio-imaging) found out that the substance accumulated in the lungs before reaching the brain suggesting that the lungs metabolize 2-CB into a different compound before reacing hte CNS.

I remember reading something about that well, but I can't remember off the top of my head where I saw it. I'd like to see the original quote again, but if your paraphrase is accurate, consider the following: the lungs generally remove serotonin from the blood stream to prevent it from reaching the heart and causing pulmonary hypertension because of cardiac fibrosis mediated by the 5-HT2B receptors. (Look into the reason that aminorex was withdrawn.) Since 2C-B is a ligand for the serotonin receptors, it makes sense that they may be sequestered in the lungs. I'd be more interested in the amount of time that the drug requires to take effect or in checking its metabolites for activity at various signalling checkpoints before jumping to the conclusion that metabolism is required.

[OFF]

Read this fantabulous thread by our late member FastandBulbous:

He's still around, AFAIK, just not moderating.[/OFF]

 

[Enkidu]

From the PNAS paper,

We found that, although dopamine alone can activate and
internalize rat 5-HT2A receptors expressed in HEK293 cells, it
does so only at micromolar concentrations high enough to argue
against having major physiological relevance.

Interestingly,
only 70–75% of the cells showed receptor internalization upon
application of dopamine, as compared with 100% for 5-HT.
The reasons why 25–30% of the cells seem to be refractory to
dopamine-mediated internalization remain to be determined.

To test whether prior exposure of 5-HT2A
receptors to serotonin would induce internalization by lower
concentrations of dopamine (5 M), SB1 cells were incubated
with 50 nM 5-HT, a subthreshold concentration for internalization,
for 10 min before the application of dopamine. As expected,
50 nM 5-HT, by itself, did not induce internalization of the
SR2-GFP receptors (Fig. 4B). Subsequently, various concentrations
of dopamine were applied in the continued presence of
5-HT for an additional 10 min, and receptors were observed to
internalize from concentrations as low as 500 nM dopamine (Fig.
4C). Thus, sensitization or ‘‘priming’’ of SR2-GFP receptors with
concentrations of 5-HT subthreshold for internalization decreased
the threshold concentration of dopamine required to
induce internalization by approx. 10-fold.

Whether signal
transduction pathways were activated or not, subthreshold concentrations
of 5-HT clearly had a priming action at the 5-HT2A
receptors, such that they require 10-fold-lesser amounts of
dopamine to cause receptor internalization and activation. This
priming is not a mere sensitization of the receptor to an agonist;
an interaction of both 5-HT and dopamine with the receptor is
essential, and it has to occur in a defined temporal sequence.
Such concentrations of dopamine as are required to internalize
the 5-HT-primed receptor are within the range of concentrations
of dopamine present at synapses in the brain. For example,
extracellular concentrations of dopamine in conscious rats has
been reported to be 1 M in rat striatum (28). Potential direct
interactions of dopamine on 5-HT2A receptors would be most
likely in areas of the brain where serotonergic and dopaminergic
neurons coexist, e.g., the ventral tegmental area (VTA) (29).
Because 5-HT receptors are most likely presynaptic to serotonergic
neurons, it is likely that prevailing concentrations of 5-HT
are sufficient to sensitize the 5-HT2A receptors before activation
by dopamine, and this could result in an altered and increased
sensitivity to dopamine. Interestingly, 5-HT2A receptors are
present presynaptically on dopaminergic neurons of the VTA,
and the interaction of these receptors with some antipsychotic
drugs regulates the release of dopamine (30). This dopaminemediated
partial activation and internalization could function in
vivo, as a partial desensitization of synaptic 5-HT2A receptors. In
addition, this process could act as a molecular AND gate,
exhibiting activity only in the presence of both 5-HT and
dopamine in a defined temporal sequence.

One mechanism by which priming could occur is through
5-HT2A-receptor multimers. Like other 5-HT receptors and
many other seven-transmembrane receptors, 5-HT2A receptors
may form multimers (31–33). It has been shown that, in some
receptor homodimers and heterodimers, binding of ligand to one
receptor site changes the conformation of the binding pocket of
the other receptor partner (34, 35). One could, therefore,
propose a model where, at subthreshold concentrations of 5-HT,
one receptor subunit is occupied by 5-HT, and the other subunit
then acquires a conformation having higher affinity for dopamine.
This situation could result in dopamine binding at lower
concentrations. Alternatively, partially activated or modified
receptor states may exist at concentrations of 5-HT that we
empirically define as subthreshold under our assay conditions.

I don't know enough about the experimental procedure to know whether dopamine receptors are expressed in tandem with the serotonin receptor in their cell line. I'm thinking not, but I don't know.. another question is whether the receptors are overexpressed. That can lead to forced oligomerization and therefore the results may be irrelevant physiologically.

 

[sekio]

That's a hypothesis, it's not a proven thing.

The luungs have a huge surface area and lots of oxygen, you do the math.

 

[Enkidu]

1 + 1 + O + radio = 2C-B(O), and then the BO floats off and activates the olfactory receptors and that's really what gets you high. Check my math, cuz this is too advanced for my four function calculator, and it doesn't make it any easier that I have to use my cock to force the radio into the calculator through the solar strip, which is busy powering my condo.

 

[nirvus]

lol. @ Endiku: i was laughing at your 2C-B(O) post and thinking, some of the kids are making fun of us hardcore nerds, but then i see it's you.
Yeah that dopamine-5ht2a thing is kind of interesting, huh? speaking of heterodimerization, i think there's even a glutamate receptor that associates with 5ht2a, maybe R2? have to chek on that.
thanks for the correct link Endiku. Lemme get busy with those images i been teasing about now . . .

 

[Enkidu]

Any news on those binding orientations?