Phenibut + GABA combined as one drug?

[KitchenChemist]

I am seeking the assistance of the members here with extensive chemistry knowledge. I have long used both Phenibut and Picamilon for Panic Attack Disorder and Generalized anxiety. Since Picamilon is essentially GABA bonded with Niacin, I got to thinking about what could be an anxiety super-drug.

The following chemical structures are Phenibut and GABA. We know that GABA supplements are useless, since GABA is produced in the brain, and orally taken GABA supplements do not cross the Blood-Brain-Barrier. However, I got to thinking.. I am looking for opinions on any way the following formulas could be combined in the same molecule (a molecule that would cross the BBB), that would separate back into Phenibut and GABA once in the brain.

Any insight would be greatly appreciated.

 

[sekio]

https://en.wikipedia.org/wiki/Phenylpiracetam ?

 

[KitchenChemist]

While I appreciate the link, I am very familiar with Phenylpiracetam. Phenylpiracetam belongs to the racetam family, and is not exactly what I am looking for. I am simply looking for a way to combine Phenibut and GABA in the same molecule, that is able to cross the Blood-Brain-Barrier AND that is able to break back down into GABA and Phenibut after entering the brain.

I am seeking some of the group's advanced chemists, to see if both of these nootropics can be combined in the same molecule. If you can refer a few of the group's chemists here, that would be greatly appreciated.

 

[sekio]

The reason I ask is, phenylpiracetam is a cyclic analog of phenibut.

I am seeking some of the group's advanced chemists,

That would be me. Bluelight is not really a drug development forum. People do this stuff for fun and we don't usually develop anything new whatsoever, it is restricted to doodles and asking what-if.

I can draw compounds until I get sick but until someone screens them in man you cannot tell before hand which will be bioactive and which won't.

There are probably a dozen or more ways of linking GABA and phenibut. here are some ideas. The ClogP is fat solubility which is a rough predictor of BBB penetration. There is phenibut gaba and picamilon at the bottom with the ClogP for comparison purposes.

How many of these have been made and tested? I don't know. I suspect the "head to tail" linkers have been done already. I also suspect they wouldn't be any more active than either compound alone; I don't think non-peptide amide bonds are broken easily. So my money is on either a fenetylline style linker with ethyl esters masking the polar carboxylic acid groups, or a propylene glycol diester.

Now you must simply find an enterprising Chinese lab to make you it, and gain the ability to verify your product independently. Good luck.

 

[KitchenChemist]

Thank you! That is exactly what I was looking for!

If you had to guess, which one do you suppose would have the best chance of penetrating the BBB, and
splitting back into Phenibut and GABA in the brain? I am thinking the first and last one... ?

Thank you sooo much for taking the time to offer me a different perspective opinion !

 

[serotonin2A]

^This is the type of situation where you really want to use preclinical models to identify a lead compound. At the very least you would want to do a comparative PK analysis in rodents, and screen them against a variety of receptors/transporters/enzymes. But it would be useful to test them in a behavioural model, to see if they are actually active and have the desired action. You can't just view these entities as prodrugs--they are new molecules that may or may not have off target actions that are very different from that of the individual components.

 

[KitchenChemist]

^This is the type of situation where you really want to use preclinical models to identify a lead compound. At the very least you would want to do a comparative PK analysis in rodents, and screen then against a variety of receptors/transporters/enzymes. But it would be useful to test them in a behavioural model, to see if they are actually active and have the desired action. You can't just view these entities as prodrugs--they are new molecules that may or may not have off target actions that are very different from that of the individual components.

Absolutely, I agree completely. I own a large colony of Mus musculus (common lab mice), and Rattus norvegicus (laboratory rats) to test some of the other compounds in behavioral models that I have tweaked over the years. (Mostly, my Mitragynine derivatives).

I know that there is no guarantee how a new molecular entity will behave in-vivo or in vitro. All I was really looking for is somebody else's opinion on bonding GABA and Phenibut in a form that would most likely lead to both secondary drugs being active, since the way that I tried it failed miserably.

Sekio, I would still like your opinion on what compound out of the list you prepared, has the best chance (in your opinion, just guesing) has the best chance of crossing the BBB AND acting as a prodrug to both GABA and Phenibut, after it enters the brain. The whole purpose of my goal here is to ensure that the compound breaks into both Phenibut and GABA once it crosses the BBB. I am thinking that the second and last compounds on your list are likely the best bets, but I would love to hear your thought. I know that it would only be a rough guest, but I am interested in hearing your thoughts none the less.

Now you must simply find an enterprising Chinese lab to make you it, and gain the ability to verify your product independently. Good luck.

I am fortunate in this regard. I am regularly in touch will several Asian labs, and I own a self-built Liquid Chromatograph, Mass-Spectrometer, Infrared/UV Spectrometer, and an Nuclear Resonance Spectrometer that I have cobbled together from spare parts over the years. (When colleges and high school labs upgrade, they sell off their old equipment for a steal).


sekio : Also, if I'm following you correctly, the following are the same compound, correct ?

 

[pinpoint]

^Indeed those two are the same. One using the hexagonal planar ring and the other using the 'Ph' symbol to denote the phenyl group.

 

[farmacista]

the fifth seems the most promising to me, but you can't know

 

[Zeds(NCO2CH2CH3)2]

Kitchen chemist you are definitely talking out of bs, you don't known a nuclear resonance spectrometer aka an NMR lol you can't just build one from spare parts

 

[KitchenChemist]

Well, you are entitled to your opinion, I suppose. The bench-top NMR unit that I purchased was bought as-is, and is an Oxford Instruments MQC bench-top NMR unit. UV/IR Spectrometers are available from just about anywhere, and the nano models are dirt cheap these days, some being the size of deck of cards. My LC and MS units are "Frankenstein" machines, cobbled together from Agilent brand components, which are built to be modular in the first place. What I mean by “assembled using spare parts” is that schools throw away some good stuff. For example, a Mass Spectrometer may have a broken vacuum pump, which can easily be replaced, or transplanted from another junk machine. The only trick is getting the software setup uniformly in some of the processing components, as older components may use different operating software. However, a few software code tweaks, and you're generally in business. Literally ANYONE with extensive computer hardware experience can accomplish this. It certainly isn't brain surgery.

However, I know the administration here likes to keep threads on-topic, and I would like to do the same.

So, seiko, the “head to tail” ethyl ester, the “head” to tail ethyl ester and acetate, the ester and benzoate, and the propylene glycol di-ester in your diagram, are probably the most promising in crossing the Blood-Brain Barrier AND in acting as prodrugs to both GABA and Phenibut in the brain? Any idea which theoretically would be the most promising out of the lot?

 

[farmacista]

theoretically has a higher ClogP should be a favourable properties to cross the blood brain barrier, but there are other unpredictable factors

 

[KitchenChemist]

Okay, so I have another questio, preferably for seiko, however all of you have been a big help, and any and all input is welcomed. So I m under the impression that the molecules on seiko's list with higher ClogP values are at least one factor in determining Blood-Brain-Barrier permeability.

However, the first two compounds on his list appear to have negative ClogP values. Is there any reason to believe that these two compounds would penetrate the BBB, and act as prodrugs to both Phenibut and GABA within the brain?

 

[sekio]

It's impossible to tell without making and testing all of these. You can't really expect to just doodle a drug and know exactly how it will behave in the body. Caffeine has a negative ClogP but it makes it into the brain fine.

Fat soluble drugs that you would expect to cross the BBB can be removed from the brain by stuff like P-glycoprotein (e.g. loperamide) which means they will have very poor BBB penetration. And highly polar compounds can be selectively transported into the brain if there's the right sort of transporter protein around (pregabalin) or if they have at least a little fat solubility at physiological pH (caffeine, ethyl alcohol). But you can't predict these things before hand, you generally need to go directly to animal models.

There's no guarantee these are even hydrolysed, peptidase enzymes may not be able to fit them into their active sites.

 

[KitchenChemist]

That's basically what I knew; I just wanted to see if you had an opinion on it, either way. That's funny, I almost brought up caffeine myself. I was also wondering what kind of pharmacology these new compounds would have if they didn't (and even if they did) act as prodrugs..

And, I know that Bluelight it not really the place for creating new drugs, but since you seem to be quite the chemistry wizard (and a GREAT help), I figured that I would ask if you see a way chemically for 5-Hydroxytryptophan and Tyrosine to be linked chemistry.. If you don't want to bother, that's fine. It just seems to me that some of the compounds would be interesting, without the need to take both separately..