Crossing the Blood-Brain Barrier

[Rorthron]

Hi,
I'm trying to compile a list of phenethylamines and tryptamines that cross and do not cross the BBB. The subject is complex and so far I could not find a straight answer or a list able to discriminate which substances do cross it.

It is of course not safe to to admit that substances that show psychedelic activity do cross it and vice-versa.

Is there a list or a site that has an annotated list of substances with this property? is it already compiled for known phenethylamines and tryptamines? Is there a way to estimate this, given the chemical structure of the molecule?

Thanks for your help

 

[MurphyClox]

It IS safe to admit that substances that show psychedelic effects cross the BBB. If they would not cross, there wouldn't be psychoactive effects.

A general rule of thumb is: The more polar (= hydrophilic) a substance, the worse does cross the BBB. A charge does imply comparably high polarity (i.e. ions of any kind); therefore do charged molecules usually not cross the BBB. Example: Muscarin, which is a permanently (!) charged quaternary ammonium compound.
On the other hand, the more lipohilic a compound, the faster resp. easier does it cross the BBB. Example: A secondary amine is less hydrophilic than a primary one (i.e. more lipophilic); ergo: Methamphetamine does have a faster onset of effects than plain amphetamine.

Exceptions from these two rules of thumb above are molecules, which indeed cross the BBB but get transported back actively, that means with energy consumption (ATP) and against a concentration gradient. Best known example: The potent opioid loperamide, which has practically no central effects.


I hope this helped for a start.

- Murphy

 

[any major dude]

^that's a more accurate and concise version of what i was going to say. I would look for phen's & trypts that aren't lipid soluble. They would be quite unlikely to cross the BBB. Also I suppose one could look for compounds that are extremely water soluble. Extensions & commentary sections in pihkal & tihkal might be a good place to start looking. I'd imagine somewhere on the internet there's a wealth of MSDS's for all sorts of chems, and if not, someone should start that project.

 

[Rorthron]

Hi Murphy Thanks for your help, that's indeed a start

It IS safe to admit that substances that show psychedelic effects cross the BBB. If they would not cross, there wouldn't be psychoactive effects.

- Murphy

Thanks. My issue with psychedelic substances not implying they cross the BBB has to do with the fact that some substances are pre-metabolyzed in other organs and their metabolites do indeed cross the BBB.

For instance my objective is to understand the unswers to this type of questions: does 4-AcO-DMT crosses the BBB, or is the acetoxy group removed metabolizing the substance into Psilocybin which does cross the BBB? Also why Serotonin do not cross the BBB if 5-HO-DMT crosses it? - on this latter question why do the 2 n,n methyl groups change dramatically the molecule's capability to enter (or exit) the brain. Is it possible to estimate, given the molecule structure, it's lipophilicity and ability to cross the BBB? So far from the published literature this seems a complex and difficult question, and I've read several studies that cover a wide range of molecules; so far none covering specifically phens or tryps. As these are relatively small molecular families I was wondering if could there be more specific rules allowing one to determine this potential. That's why I asked the experts here!

This is a really important subject in my research and I appreciate any pointers or contacts of authors who you may believe may help in this quest.

I intend to put the results of this study fully available on the internet, as soon as I have concrete data, as I believe they may be of relevance to the whole community

 

[seep]

@thread: subbed. I've been looking for a well-articulated functional exegesis of the B³ but haven't been able to find one.

And then there are a number of counterexamples to the lipophilicity dogma, or even to the seemingly-unassailable assertion that in order for a compound to have a psychological effect, it must be present in cerebrospinal fluid. Take, for example, the 1st mention of B³ in V.S. Ramachandran's Encyclopedia of the Human Brain:

Epinephrine does not cross the blood-brain barrier, but when administered peripherally it improves alertness and enhances performance on cognitive tests.

 

[any major dude]

well there are certainly ways to affect the brain indirectly. I'd imagine that the increased amount of oxygen in the blood & increased circulation consequent to administration of epinephrine could have positive impacts on cognitive functioning.

 

[seep]

^Most directly, it's epinephrine's role in the phosphorilation of hepatic glycogen, leading of course to an elevation in blood glucose. As there are no stores of glucose in the brain, this is the mechanism for epinephrine's neurostimulatory effect.

Speaking of glucose (and straying from PEAs), it has no problem crossing the B³. The reason for this is well documented, and maybe the OP can factor it into his research.

Psychoactive carbs are the future yo.

 

[greenmeanies]

mmm, drugs that are actively shuttled into the brain via enzymatic transporters...

 

[any major dude]

^Most directly, it's epinephrine's role in the phosphorilation of hepatic glycogen, leading of course to an elevation in blood glucose. As there are no stores of glucose in the brain, this is the mechanism for epinephrine's neurostimulatory effect.

Speaking of glucose (and straying from PEAs), it has no problem crossing the B³. The reason for this is well documented, and maybe the OP can factor it into his research.

Psychoactive carbs are the future yo.

interesting. i was unaware of epinephrine's specific action. That certainly would make for a much better explanation of epi's duration than my speculation regarding circulation. Does epinephrine cause either vasodilation or vasoconstriction?

 

[MurphyClox]

I'll split the post in some parts to make the answer clearly arranged:

For instance my objective is to understand the unswers to this type of questions: does 4-AcO-DMT crosses the BBB, or is the acetoxy group removed metabolizing the substance into Psilocybin which does cross the BBB? [1]
...
Also why Serotonin do not cross the BBB if 5-HO-DMT crosses it? - on this latter question why do the 2 n,n methyl groups change dramatically the molecule's capability to enter (or exit) the brain. [2]
...
Is it possible to estimate, given the molecule structure, it's lipophilicity and ability to cross the BBB? So far from the published literature this seems a complex and difficult question, and I've read several studies that cover a wide range of molecules; so far none covering specifically phens or tryps. [3]

[1] 4-AcO-DMT crosses the BBB due to its lipophilic character (clogP = 1.443). The compound gets deacetylated both before and after entering the brain, the metabolite being psilocin, not psilocybin. Psilocin is able to cross the BBB, too (clogP = 1.217). The over-all effect of 4-AcO-DMT is like an accelerated version of psilocin.

[2] Serotonin is a primary amine, while 5-OH-DMT is a tertiary one. In numbers does this mean: A difference of clogP-values of 0.629. Not dramatic, but obviously enough.

[2] I'm not aware of studies that concers PEAs or tryptamines in particular, but the logP-value can be calculated, thus resulting in the above-mentioned clogP (c for computed). All clogP-values in this post were calculated using this tool. There are several others available and the results may vary slightly.


Recommendable books on this topic are:
- Rolf Dermietzel, David C. Spray, Maiken Nedergaard : "Blood-Brain Barriers: From Ontogeny to Artificial Interfaces" (2 volume set), Wiley-VCH 2006; <DOWNLOAD>
- William M. Pardridge MD: "Introduction to the Blood-Brain Barrier: Methodology, Biology and Pathology", ; <DOWNLOAD>
- Michael Bradbury, David Begley, Jorg Kreuter: "Blood-Brain Barrier and Drug Delivery to the CNS", Informa Healthcare 2000; <DOWNLOAD>


Cheers! - Murphy

 

[Rorthron]

[1] 4-AcO-DMT crosses the BBB due to its lipophilic character (clogP = 1.443). The compound gets deacetylated both before and after entering the brain, the metabolite being psilocin, not psilocybin. Psilocin is able to cross the BBB, too (clogP = 1.217). The over-all effect of 4-AcO-DMT is like an accelerated version of psilocin.

Psilocin, Psylocybin. stupid childish mistake, damm! . I hope it was clear I was talking about psilocin!

But thanks for the info on the logP

[2] Serotonin is a primary amine, while 5-OH-DMT is a tertiary one. In numbers does this mean: A difference of clogP-values of 0.629. Not dramatic, but obviously enough.

Take a look at this:

Scott Doniger, Thomas Hofmann, Joanne Yeh. Predicting CNS Permeability of Drug Molecules: Comparison of Neural Network and Support Vector Machine Algorithms. Journal of Computational Biology. December 2002, 9(6): 849-864

The authors use the logP as a variable to try to predict BBB permeability and even with other factors, the results are not very conclusive. For the 324 molecules they test, there is not a clear relationship between logP and BBB crossing. I took the liberty of getting the data and producing a little chart with it: Take a look:

Recommendable books on this topic are:
- Rolf Dermietzel, David C. Spray, Maiken Nedergaard : "Blood-Brain Barriers: From Ontogeny to Artificial Interfaces" (2 volume set), Wiley-VCH 2006;
- William M. Pardridge MD: "Introduction to the Blood-Brain Barrier: Methodology, Biology and Pathology", ;
- Michael Bradbury, David Begley, Jorg Kreuter: "Blood-Brain Barrier and Drug Delivery to the CNS", Informa Healthcare 2000;

This is precious!!! Thanks!

[Note, for some reason, I could not even see this part of the message. I only accessed it when trying to answer you. I assumed it was because of the links, which I removed when quoting you. Let's hope they appear alright! EDIT: I can see the links now!]

all the best,

 

[MurphyClox]

The logP is just a rough estimation for the ability to cross the BBB. Exceptions are known, including some compounds that get actively transported INWARDS the brain and numerous that are transported OUTWARDS.

The psilocybin/psilocin-thing was of course just a typo. Don't mind. I'm just a bit picky sometimes


YO! - Murphy