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Questions about blood-brain-barrier

Mr Blonde

Mr Blonde

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Oct 1, 2006
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OK, so from what I've read, in order for molecules to pass the blood-brain-barrier they have to have lipid solubility. Lipids are fat-soluble molecules, right?

Secondly, the blood-brain-barrier makes it difficult for hydrophillic molecules to pass through as well.

So...

1) What is the difference between, for example, L-DOPA and dopamine that makes one lipid soluble and the other not? L-DOPA has a carboxylic acid group added...that makes a molecule lipid soluble? In all cases or just some?

Dopamine
Dopamine.gif


L-DOPA
L-DOPA.gif


2) It's difficult for hydrophillic molecules to cross the BBB...but many recreational drugs are hydrophillic. Does lipid solubility win rock-paper-scissors over the obstacles facing hydrophillic molecules?

I'd appreciate some responses, I'm a novice at this neuropharmacology stuff and I'm always trying to learn some more...would like to see the ADD neuropharmocology text get finished some day! :)
 
L-dopa crosses the BBB transported by LAT-1 (L or Large amino acid transporter) this transporter moves amino acids like phenylalanine and tyrosine across the BBB, so it has nothing to do with lipid solubility.
it is true that many centrally active are hydrophillic but most are salts which can exist as freebase at physiological pH and it is the uncharged freebase which diffuses across the BBB, there are general rules for CNS active drugs based on lipinskis rule of 5, with a few modifications. do a search for it and there is quite a lot of information where they tested the rules with known cns active drugs with pretty good results.
Things that are permanently charged tend to find it almost impossible to cross.
similarly stuff that is very lipid like gets stuck in the lipid layer and is very poor at getting into the CNS.

There are a lot of transporters that can move unlikely molecules through the BBB an of course if a transporter moves it then the molecule can be highly polar or non polar or whatever because it has another way through.
 
Ok, sweet...I just looked up a few diagrams, and L-DOPA is very similar in structure to phenylalanine, just that the latter is missing those two hydroxy groups on the aromatic ring.

I looked up Lipinski's Rule of 5, very useful information, thanks for pointing me in that direction!

So you are saying that after a salt of a drug enters the system, most of them will become freebase? And it is this freebase that is able to cross the BBB as it is uncharged/most likely hydrophobic?
 
*BUMP*

Would appreciate an answer to the above question...anyone with any knowledge on the subject?
 
Mr Blonde said:
So you are saying that after a salt of a drug enters the system, most of them will become freebase? And it is this freebase that is able to cross the BBB as it is uncharged/most likely hydrophobic?
Click to expand...

at the pH of most of the body fluids the salt will mostly be in the form of the ionised form however a very small proportion will be in the freebase it is this tiny proportion in the freebase form which is able to diffuse into lipid barriers, and then travel through, once through it turns back into the salt, so if there is a lot of salt outside the barrier then a small amount which is in the freebase form will travel across the barrier, and as more freebase is created it too will travel across. of course this also works for stuff traveling the other way, but as there is usually more drug outside rather than inside the BBB then the net effect is for stuff to travel in.
More cunning pharmacologists have designed prodrugs which can diffuse across then form permanently charged species that cannot diffuse back out.

I suggest you buy the book ' the organic chemistry of drug design and drug action' which deals with rather well with drug Absorbtion Distribution Metabolism and Excretion ADME in the jargon

V
 
Please feel obliged to have a read of the following article that I have uploaded for your viewing pleasure:

http://www.megafileupload.com/en/file/43889/BBB-pdf.html

If people want to get a wuala account then I have many journal entries which may appeal to you. I'd feel a bit less commie about this if you also have things to share, that way I get something in return for my efforts.
 
^ Thanks to both of you!

Vektor: I'll check out Amazon, see if I can get that book. :)

Smyth: Thanks for the article, I'm downloading it now...I don't have much to share unfortunately, just some diagrams I've been drawing on my computer I've uploaded to my photobucket account, with some descriptions of what they are and how they work. I think of it as a type of study aid. I've got them organized into opiods, stimulants and neurotransmitters so far, but there isn't much there. You can find if you click on my username and then click to visit my homepage. ;)

Once I've gotten a bit more in-deth with neuropharm, I'll make sure to give back to the community! :)
 
Last edited:
Lipids are fat-soluble molecules, right?
Click to expand...

Lipids are fats, therefore fat soluble molecules are lipid soluble molecules.

Adding polar functional groups to molecules makes them less fat soluble, so L-DOPA is much less fat soluble than dopamine. The polarity of common function groups, from more to less polar, goes something like:

Amide > Acid > Alcohol > Ketone ~ Aldehyde > Amine > Ester > Ether > Alkane
 
Actually, not all lipids are fats: they include oils, waxes, phospholids, steroids, cholestorols, etc.

My understanding of the polarity of a drug is thus: polar drugs are more liable to hydrogen bond and so are water soluble, which decreases their lipid solubility (measured by the water/octanol partition coefficient). Ideally, you want a drug that is not too lipid soluble, since as Vektor said they can get stuck in the lipid layers. In most of the recreational substances we abuse, this is solved by the compound becoming a freebase once it enters the blood.
 
Mr Blonde said:
Ok, sweet...I just looked up a few diagrams, and L-DOPA is very similar in structure to phenylalanine, just that the latter is missing those two hydroxy groups on the aromatic ring.

I looked up Lipinski's Rule of 5, very useful information, thanks for pointing me in that direction!

So you are saying that after a salt of a drug enters the system, most of them will become freebase? And it is this freebase that is able to cross the BBB as it is uncharged/most likely hydrophobic?
Click to expand...

Dopamine is actually synthesized from tyrosine, not Phenylalanine.
 
Yeah, and? He said that they were very similar- which they are (d-phenylalanine has been used as an amphetamine precursor.)
 
I've often wondered about L-DOPA. if the 3,4 dihydroxy function was replaced with a 3,4,5 trimethpxy, what would happen then? It's still an amino acid, so would the LAT move it through the BBB and convert it to mescaline for you?
What is the legal situation for these amino acids? In the UK, would it be legal?
 
Hehe, nice idea! Apparently the LAT will transport this thing through the attached tyrosine so it would probably transport 3,4,5-trimethoxyphenylalanine. I'm not sure about legal status though.

Large Neutral Amino Acid Transporter Enables Brain Drug Delivery via Prodrugs

Would legality be the only advantage? Or would it be more potent too, it would be resistant to MAO until decarboxylated. I guess the decarboxylase enzyme would still work on it, since apparently the same enzyme catalyses decarboxylation of all aromatic amino acids.

I don't know if it would work fast enough actually, according to wiki:

AAAD becomes the rate-limiting step of dopamine synthesis in patients treated with L-DOPA (such as in Parkinson's Disease), and the rate-limiting step of serotonin synthesis in people treated with 5-HTP
Click to expand...
 
Just an interesting fact. As drug design has become more computerized, analyzing lock and key drug enzyme simulations, drugs coming through pharmaceutical pipes have become more polar overall. As opposed to when the first tests of a drug were how well they crossed into cell cultures.
Don't have a citation only a memory from a meeting with the modelers at a pharm comp i used to work for.
The point being that its easier to get a structure that you think is going to work and then work out the BBB kinks afterwards.
 
Bump this old thread

Bumping an old thread rather than starting a new one...

vecktor said:
L-dopa crosses the BBB transported by LAT-1 (L or Large amino acid transporter) this transporter moves amino acids like phenylalanine and tyrosine across the BBB, so it has nothing to do with lipid solubility.
it is true that many centrally active are hydrophillic but most are salts which can exist as freebase at physiological pH and it is the uncharged freebase which diffuses across the BBB, there are general rules for CNS active drugs based on lipinskis rule of 5, with a few modifications. do a search for it and there is quite a lot of information where they tested the rules with known cns active drugs with pretty good results.
Things that are permanently charged tend to find it almost impossible to cross.
similarly stuff that is very lipid like gets stuck in the lipid layer and is very poor at getting into the CNS.

There are a lot of transporters that can move unlikely molecules through the BBB an of course if a transporter moves it then the molecule can be highly polar or non polar or whatever because it has another way through.
Click to expand...

Just watched one of Carl Lester's mini lectures where he says that dopamine doesn't cross the BBB because it's too polar - picks up a proton on the amine in the body. L-dopa on the other hand (he says) is zwitterionic, extra proton on the amine and an electron on the carboxylic acid, so is overall neutral and has good lipid membrane permeability. Is this just wrong..?

Why do centrally active phenethylamines, amphetamines etc cross the BBB - don't they show similar properties to dopamine, in being charged? Is it down to different pKa values, how strong or weak an acid/base they are?
 
I would expect the polarity of the two phenolic -OH groups is more of an issue, c.f. mescaline's activity in man.
 
sekio said:
I would expect the polarity of the two phenolic -OH groups is more of an issue, c.f. mescaline's activity in man.
Click to expand...

Humour me hear because my organic chem is rusty after some 10 years dormant... OH and OCH3 groups are both electron donating, right? So that should make the molecule less polar...? Compared to eg 2C-B where the bromine is electron withdrawing?
But by that reasoning 2C-B would be less likely to cross any lipid barrier.
 
The hydrogen on a hydroxyl group can form a hydrogen bond. The methyl hydrogens on a methoxy group cannnot. (I think that's what it is)
(Hydrogen bond acceptors are another thing though)

As far as I know even compounds like 4-hydroxyamphetamine, or ephedrine, which only have one OH are still much poorer at crossing the BBB than their non-hydroxylated, or masked versions.
(Aromatic ring hydroxyls are resonance stabilised, like acids, and more apt to lose their proton, so are more polar and more acidic, and hence cross BBB much worse than aliphatic OH like in ephedrine).
 
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