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Is flouro-phenibut probably as safe as normal phenibut?

D

deruyityn

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Feb 25, 2015
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Should there be no hidden surprises in this regard since flourination is such a well known 'trick' in the drug making arsenal or could there still be latent risks with this new chemical?

Its effects sound alot more appealing that the original- being purportedly shorter lasting with little to no hangover effects, quicker acting (not a big deal to me but a bonus) and supposedly slower tolerance/withdrawal inducing.

I would never usually want to be one of the first to try a new substance but is the flourination part small enough of a change that it need not be considered a radically new compound?
 
You cant know unless you do clinical trials. Even the slightest variation in chemical structure can have disastrous consequences.
 
Do you mean para-fluorophenibut (the fluoro- analogue of baclofen)? As Weltmeister said, can't know until you've done the trials, but can't see any apparent risks associated with it. C-F bonds are among the strongest bonds, especially if it's bound to an aromatic ring. My guess is that it would behave somewhere between phenibut and baclofen, but that's just pure speculation.
 
deruyityn said:
Should there be no hidden surprises in this regard since flourination is such a well known 'trick' in the drug making arsenal or could there still be latent risks with this new chemical?

Its effects sound alot more appealing that the original- being purportedly shorter lasting with little to no hangover effects, quicker acting (not a big deal to me but a bonus) and supposedly slower tolerance/withdrawal inducing.

I would never usually want to be one of the first to try a new substance but is the flourination part small enough of a change that it need not be considered a radically new compound?
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You can probably expect an increase in potency akin to phenibut -> baclofen.

Also, it should be longer lasting, as it should be metabolised slower. Can you link the source which gave you information about its pharmacokinetics?
 
Potency as what? (Yes, I get active at lower dose - but what is the pharmacology?):

Baclofen is primarily a GABAb agonist, with arguably negligible VDCC antagonism while phenibut seems to have higher selectivity for the VDCC blocking...

Is dual action really that preferable? The first question would be what F-phenibut has higher selectivity for, and if both MOAs turn out to be quite relevant, is it really interesting to basically have to combine baclofen with phenibut - drawing an oversimplified comparison?

Hard to predict whether there is beneficial synergy (worth investigating reports of people combining phenibut with baclofen), but with this sort of thing my expectations want to err on the side of unwanted interaction.
 
Solipsis said:
Potency as what? (Yes, I get active at lower dose - but what is the pharmacology?):

Baclofen is primarily a GABAb agonist, with arguably negligible VDCC antagonism while phenibut seems to have higher selectivity for the VDCC blocking...

Is dual action really that preferable? The first question would be what F-phenibut has higher selectivity for, and if both MOAs turn out to be quite relevant, is it really interesting to basically have to combine baclofen with phenibut - drawing an oversimplified comparison?

Hard to predict whether there is beneficial synergy (worth investigating reports of people combining phenibut with baclofen), but with this sort of thing my expectations want to err on the side of unwanted interaction.
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The fluoro analogue will probably (just speculating however) also act as an agonist at GABAb receptors like baclofen, presumably the reason why baclofen has much a much lower dosage.
 
That does not sound appealing, baclofen does not seem like an appropriate supplement for random healthy people like how phenibut can be used...

So is this presumed from the observed general potency of F-phenibut? Or other reasons why the electron-withdrawing nature of the halogen is more significant than the size/geometry? I mean, on average it does seem like electronegativity / polarity / log P are usually more significant than atomic radius of substitution since there are more general implications on kinetics and absorption whereas receptor fit does not necessarily have to be affected so much?
 
Solipsis said:
That does not sound appealing, baclofen does not seem like an appropriate supplement for random healthy people like how phenibut can be used...

So is this presumed from the observed general potency of F-phenibut? Or other reasons why the electron-withdrawing nature of the halogen is more significant than the size/geometry? I mean, on average it does seem like electronegativity / polarity / log P are usually more significant than atomic radius of substitution since there are more general implications on kinetics and absorption whereas receptor fit does not necessarily have to be affected so much?
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Well I was thinking more along the lines of the fact that F decreases electron density of the aromatic ring, increasing binding interactions at GABAb. Halogens don't really form strong H bonds, and F is quite small anyway.

Just a quickly thought up suggestion here: if exogenous GABA was taken by an individual, it would have lots of pharmacokinetic issues, mainly low logP, and would not reach the brain in high concentrations at all. B-alkyl (e.g pregabalin) or B-aryl (e.g phenibut) substituted GABA analogues have increased logP, so they can reach the brain in reasonable concentrations now, but it seems like GABAb activity is killed due to steric reasons (let's just suppose the binding region near the B substituent had many electronegative R groups; this would not at all favour lipophilic R groups). Substituting a halogen onto the ring drops the ring's electron density, meaning it will now still probably be a weaker agonist than GABA itself, but it now has increased affinity compared to normal lipophilic B-substituted analogues.
 
There was a thread on tolibut (p-tolyl analogue of phenibut), however, no reports of its effects. I suppose some more speculations could be made based on reports on it. =D
 
Alright some interesting discussion on the matter developing :)

belligerent drunk said:
Do you mean para-fluorophenibut (the fluoro- analogue of baclofen)? As Weltmeister said, can't know until you've done the trials, but can't see any apparent risks associated with it. C-F bonds are among the strongest bonds, especially if it's bound to an aromatic ring. My guess is that it would behave somewhere between phenibut and baclofen, but that's just pure speculation.
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Here is the developer's info on it. Is that that para-flouro version you speak of? I think I recall someone mentioning so in the second thread below; can't attest to the validity of their statement though.

aced126 said:
You can probably expect an increase in potency akin to phenibut -> baclofen.

Also, it should be longer lasting, as it should be metabolised slower. Can you link the source which gave you information about its pharmacokinetics?
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So far reports say it is shorter lasting. Isn't this the norm for flouro drugs or it just depends on the drug in question? I read they are more lipophilic so they workthrough and clear out quicker. I don't know about other drugs but I know this is the case for 2-fa; about a third of the potency of normal amp and about a 3rd of the duration.

Here are the current most comprehensive experience reports.

So far they are saying it has mostly all the good qualities of normal phenibut with the lower dependence profile of baclofen and shorter duration. Sounds great; though still cautious to try it myself being a hypochondriac.
 
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Fluoro makes it less lipophilic, more hydrophilic / more polar - but yes that eliminates it from the body quicker... the kidney tends to filter out polar compounds... Compounds that aren't polar are made polar through metabolism. There are probably a lot more criteria for renal clearance, but I think that's one of the basics..

I guess it would only be metabolized slower if the added group would interfere with enzyme activity like alpha-alkyls in PEAs. So you'd have to consider the sum of those factors, to know which one outweighs other ones if multiple apply.
 
A para fluoro would surely slow down first pass metabolism not only the side chain (by MAOs but also the ring. para-fluoro substitution block aromatic amino acid hydroxylation of phenibut which I bet to venture is probably happening. I see no reason why it won't make nice substrate for AAAH albeit it less ideal than the aromatic alfa AAs like Phe --> Tyr and Tyr---> dopamine..The resulting para-hydroxy may or may not have gaba-ergic..
 
That's interesting and could be, but is there an "advantage" of that hydroxylation if it is already fluorinated as far as excretion is concerned? Hmm never mind, seems that it is much more significant regarding metabolism.
But why fluorines would make the drug more lipophilic I don't understand.. I guess its explained here but I'm really baffled by it all. Thought i understood it a bit better.
 
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Solipsis said:
That's interesting and could be, but is there an "advantage" of that hydroxylation if it is already fluorinated as far as excretion is concerned? Hmm never mind, seems that it is much more significant regarding metabolism.
But why fluorines would make the drug more lipophilic I don't understand.. I guess its explained here but I'm really baffled by it all. Thought i understood it a bit better.
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Yes, hydroxylation increases hydrophilicity, making for easier excretion. Also once hydroxylated, the molecule can enter phase 2 metabolism where it can be conjugated to e.g. glucuronic acid, from which easy excretion follows.
 
Solipsis said:
I just don't see how a C-F bond is hydrophobic..

Van der Waals forces?. hhmm guess i wasnt the only one who found it puzzling
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922239/
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Halogen bonds are quite really quite complex in terms of lipophilicity and hydrophilicity, especially C-F bonds. Most notably, aromatic C-F bonds generally very very slightly increase lipophilicity, whereas aliphatic C-F bonds generally very very slightly increase hydrophilicity.

The aromatic substituent hydrophobicity (π,ar) is defined as the logP of the substituted benzene minus the logP of benzene. For example, methylbenzene has a logP of 2.65, and benzene has a logP of 2.13, so π,ar(methyl)=0.52. This lets us estimate e.g the logP of mephedrone, given the logP of methcathinone (just add 0.52). It normally gives you a relatively close value to the experimentally measured value.

For bromine, chlorine and fluorine aromatic substituents, the aromatic substituent hydrophobicity constants are 0.86, 0.71 and 0.14 respectively, so we can see that a decrease in atomic radius decreases the logP. For aliphatic substitents, the constants are 0.60, 0.39 and -0.17 respectively.
 
Solipsis said:
That's interesting and could be, but is there an "advantage" of that hydroxylation if it is already fluorinated as far as excretion is concerned? Hmm never mind, seems that it is much more significant regarding metabolism.
But why fluorines would make the drug more lipophilic I don't understand.. I guess its explained here but I'm really baffled by it all. Thought i understood it a bit better.
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Yes, there is an advantage because fluorobenzenes are slightly more lipophilic than benzenes anyway. Even if fluorine made the aromatic ring slightly more hydrophilic, there would still be a massive advantage in ring hydroxylation, because hydroxylation then allows very favourable phase 2 conjugation metabolic reactions, which allow the compound to be excreted very easily. For example, morphine underdoes phase 2 metabolism to morphine-3-glucuronide and M-6-G.
 
Going back to the OP is there any more to comment about its probable safety or lack thereof? Just a wait and see thing? Is it not so easy to just infer that other drugs are commonly flourinated and are safe so this one is no different or does it have to be a case by case basis?

Some people have assayed it without issue. Been out around 4 - 6 months without negative complaints so far. Or is it too early to say with any confidence. I know it isn't much data; the more the better of course but talking on a probability scale.
 
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Is it not so easy to just infer that other drugs are commonly fluorinated and are safe so this one is no different or does it have to be a case by case basis?
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generally speaking, close relatives of existing drugs have similar tox/activity profiles, but it's hard to say without empirical testing.

In cases where fluorination blocks a metabolic site (e.g. 4-F-Amphetamine, 4'-f-methylphenidate) the duration/potency is generally increased as you effectively disable one of the possible routes it gets inactivated

Aren't baclofen, phenibut and friends limited in their uptake into the CNS due to their polar amino-acid type structure? In that case there's another variable to consider - affinity for the active transport proteins which bring it to the receptors. If you increase the affinity in vitro but cripple the compound from makign it into the brain, your drug ain't gonna be more potent per mg!
 
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