5 replies to this topic

[Reformed-Redan]

Found a pretty intriguing natural flavonoid compound for ADHD. It's more potent than Ritalin at dopamine reuptake and is non habit forming. Anyone interested in this for ADHD and nootropic purposes? 

 

I already got a quote for 1 kg of this compound. 

 

If anyone is interested in a group buy let me know.

 

http://www.ncbi.nlm....pubmed/23707903

 

[dwaaam]

Seems interesting!

Do you know if it affects BDNF like Oroxylin A?

How much is the kilo price according to the quote?

[Reformed-Redan]

Seems interesting!

Do you know if it affects BDNF like Oroxylin A?

How much is the kilo price according to the quote?

 

Yea,

 

I'm pretty sure it affects BDNF like Oroxylin A along with probably being a negative allosteric modulator at GABA sites, promoting wakefulness and memory consolidation. 

 

The rough cost for 1 kg would be around $12k, not unreasonable and totally within the reach of say 20+ participants. I also think irc.bio might be able to cover some of the costs of synthesis. 

[normalizing]

so is this completely new synthetic derivative of oroxylin or what? isnt it better to go for the better known oroxylin type which is likely much less expensive?

[Oracle Laboratories]

One of the associates that I work with has been interested in the Oroxylin and related flavones and flavanoid derivatives for a while, and assembled a study proposal for our research board to review.  Although I partially have a say in that decision, it is not entirely up to me, but I have been impressed by some of the recent work on Oroxylin A and related Baikal Skullcap flavones for a while.  I certainly think that someone should look at further derivatives of this compound, and explore altering the functional group(s) and their affinities for various target binding sites.

Just a few thoughts that come to mind regarding the immediate usage of this compound (5,7-Dihydroxy-6-methoxy-4'-phenoxyflavone) for therapeutic or research purposes in human subjects).  Has anybody read the entirety of the study rather than just the abstract?  I am no position to tell anyone not to experiment (typically being the first human test subject to test many of our compounds in-vivo), but aside from this publication, I have not much of anything else regarding this compound's use.  I have a PubMed paygate pass, and I will read over the full study when I get a chance and report back.  I am very interested in what compounds this research compound may produce metabolically, and whether those potential metabolites have any significant adverse activity to any neuronal systems.  (Remember, the enzymatic proteases and gastrointestinal cytochromes for metabolism vary between mice and rats, let alone human beings)!  Whenever a compound is developed by one of our teams, for example, very extensive metabolic assays are performed in animal tissues and then in cloned or simulated human neuronal cell types in-vitro, to assure that there are no potentially neurotoxic metabolites produced, and that we understand the action(s) of any metabolites, before they are tested by a human subject in-vivo.  I certainly understand people's enthusiasm, and I am a  psychonaut myself, but please, always assemble as much in-vitro and in-vivo animal and human model data as possible, before simply trying a compound that sounds really good (without much research or history of use) on yourself and all of your friends. (Making sure that you have the adequate background knowledge to fully interpret the text(s)).  I really am not trying to preach; I am simply advising all of you to be cautious.  Remember, we still do not have a whole lot of data on what cytochromes and enzymatic proteases are responsible for Oroxylin A's metabolism, let alone a derivative.  However, much more is published regarding Oroxylin A pharmacology and pharmicokinetics (at least in animal models), so if you are going to try this compound, I'm going to go with normalizing's suggestion to just try and obtain pure Oroxylin A before trying this derivative compound, at least until a bit more information is available.  (Again, I will review the full publication and report back when I have time).

I have a few thoughts about some of the pharmacokinetic potentials of human metabolism, simply based on the chemical structure of this compound compared to Oroxylin A alone. First, the full IUPAC chemical name listed in the PubMed study along with the accompanying chemical structure posted in this thread are a bit misleading.  Based on what I consider logical alterations to make to the Oroxylin A molecule, along with the accompanying chemical structure diagram, I have copied the image and made a clarified version based on what I interpret to be the synthesis path that the development team would have followed in building this compound. (With a remaining bit of lacking clarity regarding the full IUPAC name listed in the PubChem study and the reason why the following clarified version wasn't the one depicted by the authors).

[LEFT] ​This is Oroxylin A  |  [RIGHT] Simplified version of the new 5,7-Dihydroxy-6-methoxy-4'-phenoxyflavone (based on what I consider to be a logical (somewhat,  ) alteration of the Oroxylin A molecule. (Despite the slightly misleading IUPAC name and the chemical structure depicted in the study) :

        
                         

I won't go into too much detail regarding Oroxylin A, since there is a bit of literature out there regarding it's chemistry and pharmacology in-vitro and in-vivo, at least in animal models. However, I will point out a few things:  The cyclic phenyl ring that extends off of the right side of the Oroxylin A molecule is likely the carrier-moiety that allows the compound to be lipophillic enough to penetrate the Blood-Brain-Barrier.  This in itself should be pretty efficient (especially if the binding data for the DAT (Dopamine Transporter) is accurate) - so one has to wonder why the first alteration that the authors of the 5,7-Dihydroxy-6-methoxy-4'-phenoxyflavone study made was to add what I interpret from the slightly misleading chemical name and posted diagram, a phenoxide group (an additional phenyl ring separated by an oxygen atom, which may help improve Blood-Brain-Barrier crossing, but likely will just be cleaved metabolically via first-pass metabolism in the stomach and/or gastrointestinal tract anyway, long before noteworthy levels of absorption occur, and before systemic circulation. - (Either the entire phenoxide group including the oxygen, or possibly just the phenyl ring, leaving the bare oxygen).  

Also, the hydroxyl groups (HO, OH - marked in blue) are likely to be cleaved metabolically via first-pass metabolism by certain digestive cytochromes in the gut in both compounds.  So, without knowing which enzymes are responsible for breaking down the entire molecule in humans, a few things could occur where those hydroxyl groups are cleaved: *they could be hydrolyzed, leaving bare hydrogen atoms in place of the hydroxyl groups, *they could be oxidized, leaving bare oxygen atoms in those positions, *they may be oxidized and then hydrolyzed again - creating the same original hydroxyl groups which may survive first-pass metabolism and survive past absorption, *and a dozen or so other different metabolic changes at those positions - all of which are going to alter the polarity of the overall molecule, and subsequently it's binding affinity for the Dopamine Transporter and possible other sites.  So far, we have evidence in several studies that show that when Oroxylin A is administered Dopamine-Reuptake occurs.  What we're not 100% clear on, is whether it is Oroxylin A's structure in whole, or an active metabolite that is responsible for this action, as their hasn't been a lot of work on all of the possible metabolic pathways in rodents, let alone humans. (And there are differences).


The simplified version of the new 5,7-Dihydroxy-6-methoxy-4'-phenoxyflavone (based on what I consider to be a logical (somewhat,  ) alteration of the Oroxylin A molecule. (Despite the slightly misleading IUPAC name and the chemical structure depicted in the study) :

 

        

 

As stated above, depending of which enzymes are responsible for the first-pass metabolism of these compounds (and in what particular order), a lot can happen metabolically to the polar hydroxyl groups (HO, OH - marked in blue).  Additionally, the (what I interpret to be a phenoxide group based on the vague chemical structure and IUPAC name depiction in the cited study, marked in red) may assist in Blood-Brain-Barrier crossing, but if I had to guess is probably cleaved metabolically via first-pass metabolism in the gut or GI tract (either the entire phenoxide group (the oxygen and the additional phenyl ring), or just the phenyl ring, leaving the bare oxygen atom.  If this is the case and the bare oxygen remains, my curiosity immediately goes to what this group could become via further first-pass metabolism, and even via secondary metabolism - as this could easily become a polar-orienting group, affecting the compound's overall binding affinity for particular targets in the brain, and since these compounds have some action at the Benzodiazepine Binding Site on GABA -A Receptors (which we know from the benzodiazepines and drugs like zolpiden and zopiclone) can be a target that significantly alters Central-Nervous-System function, I would be a bit hesitant in testing them, in-vivo in humans, without a bit more pharmacokinetic data regarding the metabolic pathways utilized by these compounds in humans.

Also, remember that benzodiazepines, despite exerting an agonist action at the Benzodiazepine Binding Site on the GABA -A Receptor (which excites chloride channels directly), they also function as Positive Allosteric Modulators to GABA itself, by enhancing the action of GABA that binds at the GABA Binding Sites on GABA -A Receptors.  A drug with a strong Negative Allosteric Modulator action at the Benzodiazepine Receptor Binding Sites could be a highly stress-inducing and unpleasant experience.  Because of the unknowns regarding 5,7-Dihydroxy-6-methoxy-4'-phenoxyflavone's full metabolic picture (particularly regarding that phenoxide group, and what could become of it in-vivo), I would stick with the naturally-occurring Oroxylin A if you guys do absolutely have your minds made up regarding trying one of these compounds.

I will read over the entire publication when I have time.  I definitely would like to see someone explore this class further, but for now, there is a fair bit of data lacking. Just some friendly advice for now.

 

 

 

 

 

 

-J. Gona

Oracle Laboratories
NeuroPsych Institute

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[Reformed-Redan]

Also, remember that benzodiazepines, despite exerting an agonist action at the Benzodiazepine Binding Site on the GABA -A Receptor (which excites chloride channels directly), they also function as Positive Allosteric Modulators to GABA itself, by enhancing the action of GABA that binds at the GABA Binding Sites on GABA -A Receptors.  A drug with a strong Negative Allosteric Modulator action at the Benzodiazepine Receptor Binding Sites could be a highly stress-inducing and unpleasant experience.  Because of the unknowns regarding 5,7-Dihydroxy-6-methoxy-4'-phenoxyflavone's full metabolic picture (particularly regarding that phenoxide group, and what could become of it in-vivo), I would stick with the naturally-occurring Oroxylin A if you guys do absolutely have your minds made up regarding trying one of these compounds.

 

 

It might be stress inducing as you say; but, at the same time the antagonism at GABAa receptors likely is a confounding factor in the ability of Oroxylin A to enhance memory formation.

 

Here is a really great study on the effects of flavonoids and various terpenes on GABA activity and how that might affect cognition.

 

http://sydney.edu.au...efsPDFs/376.pdf

 

Also,

 

https://en.wikipedia...a.org/wiki/Α5IA