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Kavain - the prototype of a new class of 'novel' GABA ligands

I had the chance to try kavain and 500mg produced quite euphoric effects lying somewhere between pyrazolam (anxiolytic) and ethanol. But KEY was that unlike ethanol, it doesn't appear to have significant a1 activity which as another BLer found (in papers) that a1 PAM produces dopamine disregulation which I can absolutely understand as a good reason for people becoming dependent on alcohol.

Now, I spent MANY hours looking at the synthesis of kavain. It's one of those targets where their isn't a key step that is really problematic but rather it takes 4 or 5 steps (from commercially available compounds) and as people know, while 64% yield doesn't sound bad... but even with 4 steps means a woefully low overall yield.

Noe Kava may even be legal in the UK under the classification of a 'traditional herbal medicine' but if a bottle/can/tolerant person standing on their head with a solution of the active in their armpit don't represent a financial problem... the production of kavain with it's modest activity IS an issue.

The papers I've pulled all seem fine but it's a 4 or 5 step synthesis with yields in the 60-70% yield. Now in chemistry, that's considered a 'good to high' yield for ONE step. But suddenly, 65% yield (for example) means 0.56 x 0.65 x 0.65 x 0.65 (and possibly x0.65).

As you can quickly calculate. A low overall yield.

So I'm quite keen to know if anyone has discovered a better route OR, for example, a biosynthetic route.

Kavain seems to me to be a really practical alternative to alcohol. Duration is 4-6 hours and importantl and like medicines such as clobazam, taking more doesn'r increase the subjective effects. Those same effects simply last for longer.

It strikes me that kavain is a really good alternative to ethanol but it is by no means cheao.

As some people know, I developed pyeyzolam and while a learning experience, we discovered that it emulates 'drunk' very well BUT it is of no use in emulating a couple of bottles of beer or a couple of glasses of win (for example).

I very much am looking for input from you, BLers. We DID manage to produce an alcohol mimic that did manage to emulate a bottle of beer to a bottle of vodka... but it's a synthetic drug. Kavain, being natural and very safe strikes me as a much more likely product to be accepted.
 
Well as i'm only just learning the very basic fundamental's of Organic chemistry let alone chemistry itself im afraid I can be absolutely no help at all. But since this is something im really wanting to learn I was eager to read about your partin the dev of Pyeyzolam, super fascinating, man. In a team led by Leo Sternbach?? Correct if wrong. May I ask off topic quickly how you secured a position at that particular Pharma Company, as in from an academic standpoint what steps did you first take to get started in the ''drug discovery scene'' ??? I am admittedly lost in which way to go so all im doing for new is just studying a great free Organic textbook by John McMurry, thats all ive got. Anyway, off topic but even if you wanted to PM me at any time you're free, eager to absorb as much wisdom as I possibly can, and you seem very active and pretty fucken on to it from what i've read. P.S I have a pack of Kava in my cupboard, very popular here, especially among Polynesians, is a very strange buzz, feels far more like a ''tool'' or what some would describe as ''spiritual'' in terms of its drunken effects comparing to that of alcohol imo.
 
Isn't kavain only present at a decent volume in certain strains, or did you take an extract?
I once took a 30% kavalactone extract or something, and when I'd dose it significantly higher than it should've been it felt like literal MDMA, at least for a little while, then it turned into warm and fuzzy sedation. Worth noting this does bind to the CB1 receptor. I got this extract again at one point and it never did a thing. Pretty sure all the batches just went bunk or something, someone on reddit recently reached out about it and said they never felt anything.

Kava can be very on and off but I usually feel it every time. Not much right now though, took 15g micronized, haven't had kava for months beyond capsules from headshops, which are OK but would be equivalent to like, 0.5g micro if I had to guess.
 
The sample I tried was synthetic but I agree that for a short time I did get that MDMA-like lovedup feeling. It passed fairly quickly and I admit, I was a bit gutted.

It may be that some of the other lactones that don't individually seem to be substantially active ARE active if a mixture is consumed?

I freely admit to being a coward. I took a sample of the pure material because I had heard bad stories about the 'natural' extracts.

Their IS a compound that bears a 3,4-MD ring substituent but as I'm sure you know, that ring isn't some kind of magic that ensures MDMA-like activity. Their are also two lactones which have a p-MeO substitution and those could equally produce SERT activity.

BUT to be clear - it's valuable that people post their experiences. In no way am I suggesting that my experience was the best or even that it was typical.
 
AlsoTapered said:
I freely admit to being a coward. I took a sample of the pure material because I had heard bad stories about the 'natural' extracts.
Click to expand...

There were some problems related to kava extracts sold in pharmacies over here in the early 2000s. They seemed to be hepatotoxic. This problem did only arise with the extracts afair and was never related to pure kava powder.
 
izo said:
There were some problems related to kava extracts sold in pharmacies over here in the early 2000s. They seemed to be hepatotoxic. This problem did only arise with the extracts afair and was never related to pure kava powder.
Click to expand...

Forgive me for being a mite vague but I think I read it was because some manufacturers were harvesting the entire plant. The traditional method only used the roots of the plant:

pubmed.ncbi.nlm.nih.gov

In vitro toxicity of kava alkaloid, pipermethystine, in HepG2 cells compared to kavalactones - PubMed

Kava herbal supplements have been recently associated with acute hepatotoxicity, leading to the ban of kava products in approximately a dozen countries around the world. It is suspected that some alkaloids from aerial kava may have contributed to the problem. Traditionally, Pacific Islanders use...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

It's interesting that while the above study seems to identify the toxin, other sources suggest that the amounts found in the plant would be insufficient to be toxic.

It's the fact that the toxicity isn't well studied that made me put my hand in my pocket and pay for a pure compound. I thought MAYBE it could be a new RC but the synthesis of kavain has never been optimized and even after spending a couple of weeks looking, I couldn't find a CHEAP way to produce it.
 
From the profile, it seems to be more like topiramate than ethanol. Maybe even gabapentin. Lots of VGIC blocking.
 
AlphaMethylPhenyl said:
From the profile, it seems to be more like topiramate than ethanol. Maybe even gabapentin. Lots of VGIC blocking.
Click to expand...

If you look, I've just read all the papers and patents in which the opioid activity of tianeptine is screened. One example proved to have a MOR affinity >160 times that of tianeptine.

It's useful for those seeking to build a training set but the thing to beware of is the unknown. we don't know if 7b is, like tianeptine, a superagonist. It might be an agonist, partial agonist, silent agonist, inverse agonist or antagonist. But a superagonist with a MOR Ki of just 1.2 represents a potentially dangerous compound.
 
I've consumed ethanolic kava extracts on and off for a while, never had any inkling of toxicity. I'm guessing it was an issue with as mention, wrong parts of the plants used or tudei kava that I've heard nasty things about
 
Unusually, kavain IS available in the UK since it technically falls under the 'traditional herbal medicine' loophole of the PSA.

The problem is that kavain is a bit of a pig to make when you realize that it isn't very potent.


Now, Ethyl (5R,6E)-5-hydroxy-3-oxo-7-phenyl-6-heptenoate (the immediate precursor) does turn up in ChemSpider under various names suggesting it has turned up in a number of syntheses BUT unless their is some as yet unidentified natural source or it's used (in quantity) for the production of something else, it's pretty much a dead end.

Library Genesis

libgen.li libgen.li

There are other routes but they require six or seven steps. As it is, it looks like nobody has sought to improve the synthesis for some 36 years.

It's such a shame because kavain appears to be a decent and safe psychoactive... but few RC vendors really care about making a SAFE product.
 
AlsoTapered said:
If you look, I've just read all the papers and patents in which the opioid activity of tianeptine is screened. One example proved to have a MOR affinity >160 times that of tianeptine.

It's useful for those seeking to build a training set but the thing to beware of is the unknown. we don't know if 7b is, like tianeptine, a superagonist. It might be an agonist, partial agonist, silent agonist, inverse agonist or antagonist. But a superagonist with a MOR Ki of just 1.2 represents a potentially dangerous compound.
Click to expand...
I'm a bit confused here. Sorry.
 
AlphaMethylPhenyl said:
I'm a bit confused here. Sorry.
Click to expand...

My bad - wrong thread!

Are people aware that raecemic kavain (actually, I'm not certain if the (S) isomer is even CALLED kavain but their is no agreed upon term) and it was as effective as oxazepam.

pubmed.ncbi.nlm.nih.gov

[D,L-kavain in comparison with oxazepam in anxiety disorders. A double-blind study of clinical effectiveness] - PubMed

In a placebo-controlled double blind clinical trial, 38 out-patients with anxiety associated with neurotic or psychosomatic disturbances were treated with D,L-Kavain (Neuronika) or Oxazepam. The anxiolytic effectiveness of the two preparations was judged by means of the Anxiety Status Inventory...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

The closely related 5,6-dehydrokavain IS noted to be an MAOI. A property that's always a concern in drug discovery.
 
AlsoTapered said:
My bad - wrong thread!

Are people aware that raecemic kavain (actually, I'm not certain if the (S) isomer is even CALLED kavain but their is no agreed upon term) and it was as effective as oxazepam.

pubmed.ncbi.nlm.nih.gov

[D,L-kavain in comparison with oxazepam in anxiety disorders. A double-blind study of clinical effectiveness] - PubMed

In a placebo-controlled double blind clinical trial, 38 out-patients with anxiety associated with neurotic or psychosomatic disturbances were treated with D,L-Kavain (Neuronika) or Oxazepam. The anxiolytic effectiveness of the two preparations was judged by means of the Anxiety Status Inventory...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

The closely related 5,6-dehydrokavain IS noted to be an MAOI. A property that's always a concern in drug discovery.
Click to expand...
Maybe I'm playing devil's advocate here a bit, but there are some shortcomings. This is one RCT, not an MA or SR. And it's over 30 years old. From an institution that I would call nebulous. We just have the abstract, as I can't at least find the full text, so we don't really know if it's short-term or long-term efficacy that's proven, and that makes a big difference. To say nothing about the rigor of their functions used. From the length of the abstract, too, four sentences, it's hard to derive anything about their methods. just food for thought here.

This one might be more up to date: https://www.researchgate.net/public...py_of_Anxiety_Disorders_Promises_and_Concerns
 
AlsoTapered said:
If you look, I've just read all the papers and patents in which the opioid activity of tianeptine is screened. One example proved to have a MOR affinity >160 times that of tianeptine.

It's useful for those seeking to build a training set but the thing to beware of is the unknown. we don't know if 7b is, like tianeptine, a superagonist. It might be an agonist, partial agonist, silent agonist, inverse agonist or antagonist. But a superagonist with a MOR Ki of just 1.2 represents a potentially dangerous compound.
Click to expand...
This won’t be helpful and I apologize but Tianeptine, in my experience, has worked while I’ve been prescribed buprenorphine 8mg 2x daily, so I’d have to assume it’s even more “sticky” to those receptors than bupe and it’s crazy “sticky”. Im admitting my ignorance by posting this and side tracking you simultaneously so I apologize
 
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