Benzos Ethylbromazolam

[Working_Class]

I've seen this on a vendor recently and am wondering what the difference might be pharmacologically. Any ideas?

 

[4DQSAR]

I cannot even find the structure of this alleved 'novel' benzodiazepine.

If the 2-methyl moiety has been swapped for the 2-ethyl, I suppose it will be active but less potant than the parent drug. My guess that this is the modification is based on the fact that if someone is making bromazolam, they only need to alter one simple precursor.

It also underlines the fact that the maker only has a shaky grasp of the QSAR of benzodiazepines. Mecolonazepam is the sole example of a benzodiazepine with a 3-methyl moiety. While most synthesis would produce the chiral product, the increased potency would more than offet the issue. That 3-methyl could be added to almost every RC benzodiazipine I know of. If someone is prepared to go chiral - the (R) enantiomer had an increadibly high affinity for certain GABA receptor subtypes (I read a table of affinity data decades ago).

 

[pcplease]

seems to be the first chinese novel benzo rc- i wonder if itll lead to ethylclonazolam and so on

reports seem mixed; ill probably try it.

 

[Esperighanto]

I cannot even find the structure of this alleved 'novel' benzodiazepine.

If the 2-methyl moiety has been swapped for the 2-ethyl, I suppose it will be active but less potant than the parent drug. My guess that this is the modification is based on the fact that if someone is making bromazolam, they only need to alter one simple precursor.

It also underlines the fact that the maker only has a shaky grasp of the QSAR of benzodiazepines. Mecolonazepam is the sole example of a benzodiazepine with a 3-methyl moiety. While most synthesis would produce the chiral product, the increased potency would more than offet the issue. That 3-methyl could be added to almost every RC benzodiazipine I know of. If someone is prepared to go chiral - the (R) enantiomer had an increadibly high affinity for certain GABA receptor subtypes (I read a table of affinity data decades ago).

You're spot on about R-2 being the substition point, according to some initial testers on other platforms it's ~1/2 the potency of bromazolam, and specifically it's far less sleepy. I'm curious if the duration is down at all though, brom's duration was always a pain in my ass. I binged it exactly once, 24mg, and was barred out through the entire next day and into the morning after that.

 

[4DQSAR]

It's crazy to me that Professor James T. Cook at Milwaukee Institute for Drug Discovery spent over a DECADE working out the QSAR of the 1,4 benzodiazepines. It's DONE! It's ALL DONE!

BTW I did not get on with 'Captain Cook' as he likes to be known as - too much ego. He's a good friend of David Nutt which came to NO surprise to me when I learnt. They were just fawning on each other about how wonderful it was to discover an alcohol mimic.

Nutt was careful NOT to mention that in fact HE didn't design pyeyzolam, someone else did.

Truly - they should get married and have done with it... the inevitable divorce would be SPECTACULAR to watch.

But yeah - Cook has done it ALL yet not one RC vendor appears able to read Cook's work. So do we trust the vendors, kids?

​

 

[pcplease]

they are so far removed from drug culture that without seeing them first appear in the EU, we now have this ethylbromazolam, lol. i dont think they have incentive to try to branch out. brom was so close and so prevalent/dominant the last 3-5yrs as fake bars. ethyl alprazolam might be their next logical choice

not to mention the other good ones that CN has previously made. fluclotizolam was excellent. that said i would not be opposed to any of the abovementioned Cook novelties

 

[Esperighanto]

It's crazy to me that Professor James T. Cook at Milwaukee Institute for Drug Discovery spent over a DECADE working out the QSAR of the 1,4 benzodiazepines. It's DONE! It's ALL DONE!

BTW I did not get on with 'Captain Cook' as he likes to be known as - too much ego. He's a good friend of David Nutt which came to NO surprise to me when I learnt. They were just fawning on each other about how wonderful it was to discover an alcohol mimic.

Nutt was careful NOT to mention that in fact HE didn't design pyeyzolam, someone else did.

Truly - they should get married and have done with it... the inevitable divorce would be SPECTACULAR to watch.

But yeah - Cook has done it ALL yet not one RC vendor appears able to read Cook's work. So do we trust the vendors, kids?

​

I'm going to spend today diving into these two peoples' academic literature, but I'm curious, given their egos, are their publications peer reviewed? Also, where did you hear on the ego issues? Not trying to discredit or anything, but if there are further resources to learn about these chemistry like a conference speech or something I'm just curious about if it's on YouTube.

 

[LucidSDreamr]

brom was so close and so prevalent/dominant the last 3-5yrs as fake bars.

Is brom out of circulation or scheduled? I always wondered what was in most of these fake bars.

 

[4DQSAR]

I'm going to spend today diving into these two peoples' academic literature, but I'm curious, given their egos, are their publications peer reviewed? Also, where did you hear on the ego issues? Not trying to discredit or anything, but if there are further resources to learn about these chemistry like a conference speech or something I'm just curious about if it's on YouTube.

Met them both.

The science is extremly good and amazingly comprehensive. I wouldn't have mentioned it otherwise.

But they LIKE to be in the limelight all the time. They are both essentially trying to sell their respective research on the basis of their fame. They neglect to mention that in fact it was the work of dozens of people. I don't expect a name-check of teams, but to infer that they are everything seems unfair to their respective teams.

GABA Labs has a page on it's website saying that people seeking to invest £50,000-£100,00 thousand click <HERE>, people seeking to invest £100,000-£250,000 click <HERE> and people seeking to invest >£250,000 should click <HERE>. When you specifiy sums in such bands - it's just trying to give the impression that they are being overwhelmed with investors. But you check Companies House to discover it's just Alcarelle renamed. Apart from Nutt and Orren, everone else resigned.

I just don't think they will ever get a product to market. I just don't see a pathway to do it and they haven't ever suggested a path. But as long as people keep on buying shares...

 

[pcplease]

brom got banned in China last June or july and bars are finally drying up. it has been the dominant one bc it feels very similar to alp. much closer than flualp.

the immediate replacement was phenazolam which i love but with a 2hr+ onset and 24hr+ duration is ridiculous to pass off as alpraz. the heavy bartards generally like them bc therapeutically, they work very well for a very long time without excess sedation or next day rebound anxiety. ethylbrom is starting to become more widely available and i assume overtake popularity. but i imagine phenazolam has made enough fans to stick around for a while. it may be more subtle than alp or brom but stable, longlasting calmness

 

[LucidSDreamr]

But they LIKE to be in the limelight all the time. They are both essentially trying to sell their respective research on the basis of their fame.

Sounds like they are high on their own supply.

Interesting drugs are sought out and the IP acquired by or licensed to pharma companies. These things don’t need to be sold. They are sought after by companies and they will find them. Maybe there just isn’t a need for more benzos. We already have quite a nice variety of them in medicine.

 

[4DQSAR]

Sounds like they are high on their own supply.

Interesting drugs are sought out and the IP acquired by or licensed to pharma companies. These things don’t need to be sold. They are sought after by companies and they will find them. Maybe there just isn’t a need for more benzos. We already have quite a nice variety of them in medicine.

Well, I suggested that they get pyeyzolam licenced as a treatment for alcohol dependence then go on to prove the inherent safery and from there lobby for it to be a [P] medicine.

But that would cost billions. The alcohol industry would most certainly have this thought out so you would expect them to fight it every inch of the way. But as it is, it's more or less a memecoin. You aren't buying into a business with a plan to release a product. You buy hoping that at some point a press release or TV interview will push that share-price higher than you paid for it. But I'm 100% sure IF the alcohol industry was concerned, they would click on the >£250,000 link, ask for the tour, find out what's going on and not buy the shares.

 

[tryptakid]

I still have a few bromazolam bars... never liked them much - too heavy.

Tiz is all I really ever want out of a benzo. Occasionally I'll use a very low dose of nitrazolam for sleep in an emergency

 

[LucidSDreamr]

Well, I suggested that they get pyeyzolam licenced as a treatment for alcohol dependence then go on to prove the inherent safery and from there lobby for it to be a [P] medicine.

But that would cost billions. The alcohol industry would most certainly have this thought out so you would expect them to fight it every inch of the way. But as it is, it's more or less a memecoin. You aren't buying into a business with a plan to release a product. You buy hoping that at some point a press release or TV interview will push that share-price higher than you paid for it. But I'm 100% sure IF the alcohol industry was concerned, they would click on the >£250,000 link, ask for the tour, find out what's going on and not buy the shares.

Why is pyezolam superior for alcohol dependence vs any of the existing benzos or baclofen?

 

[4DQSAR]

Why is pyezolam superior for alcohol dependence vs any of the existing benzos or baclofen?

It's a selective a5 ligand.

Alcohol primarily binds to the a1 and a5 subunits. But it was quickly discovered that the amnesia, mood lability, syncope and loss of exective function were all mediated by the a1 subunit. BUT it fully substituted for alcohol in dependent users - you don't WANT a drink if you take pyeyzolam.

In non-depndent users, pyeyzolam essentially has no effect whatsoever until you reach about 20mg but then from 20mg to 30mg is like going from a glass of wine to a bottle of wine. But obviously for detoxification, you need much less.

The design even considered the chemical in Tipplersbane mushrooms (1-aminocyclopropan-1-ol) and including that in the formulation so if a patient drinks just a little alcohol... they have uncomfortable symptoms. The design was DONE, but that pathway was considered too costly. But I don't see how a drug can be given a GSL (general sales licence) until it's safety and efficacy had been proven beyond reasonable doubt in a medical setting. I asked and was told that the issue would be considered at some time in the future. That was a decade ago.

 

[LucidSDreamr]

That was a decade ago.

That’s about half the patent term being lost by this point. That’s a lot of money and a turn off to investors.

Thanks for the explanation of how it works

 

[pcplease]

it is interesting to me, as well, though i have no idea how long it's been since the last new Rx US pharma bzd was around. im not sure how new it is, but Mexazolam (brand "Melex") from Japan has some popularity behind it. Main metabolites Delorazepam and lorazepam IIRC

 

[4DQSAR]

That’s about half the patent term being lost by this point. That’s a lot of money and a turn off to investors.

Thanks for the explanation of how it works

It's too late - it takes an average of 13 years for a medicine to get through the development process so by the time it reached market, others could simply produce a generic.

HOWEVER

That was the first generation. The second generation are code-named 'The Supercats' and those, those are only known to a handful of people.

It quickly became apparent that the dose-response curve was far from ideal and it was recogonized that the 1,4-benzodiazepines only bind to the β1γ2 unit and you need to go for the β2 and β3 so the compound binds to ALL the a5 sites alcohol does. It's clear that at low doses alcohol binds to those latter units and it's only at higher doses when the a5β1γ2 subunit is important i.e. when you get drunk. So fine for alcoholics... but not fine for someone who seeks 'a couple of glasses of wine' levels of intoxication.

That's also been done and in a single molecule. Previous efforts meant a minimum of two compounds which would have instantly doubled development costs so Nutt wasn't even interested. But AFTER departing Alcarelle, a way to produce a single water-soluble compound was discovered. It works. But then the money ran out and nobody is going to go on with it without investment.

That is the usual result of drug development - the MAJORITY of medicinal chemists never even get a single compound to market over their entire career. So move on and do the next thing is all anyone can do.

 

[LucidSDreamr]

It's too late - it takes an average of 13 years for a medicine to get through the development process so by the time it reached market, others could simply produce a generic.

HOWEVER

That was the first generation. The second generation are code-named 'The Supercats' and those, those are only known to a handful of people.

It quickly became apparent that the dose-response curve was far from ideal and it was recogonized that the 1,4-benzodiazepines only bind to the β1γ2 unit and you need to go for the β2 and β3 so the compound binds to ALL the a5 sites alcohol does. It's clear that at low doses alcohol binds to those latter units and it's only at higher doses when the a5β1γ2 subunit is important i.e. when you get drunk. So fine for alcoholics... but not fine for someone who seeks 'a couple of glasses of wine' levels of intoxication.

That's also been done and in a single molecule. Previous efforts meant a minimum of two compounds which would have instantly doubled development costs so Nutt wasn't even interested. But AFTER departing Alcarelle, a way to produce a single water-soluble compound was discovered. It works. But then the money ran out and nobody is going to go on with it without investment.

That is the usual result of drug development - the MAJORITY of medicinal chemists never even get a single compound to market over their entire career. So move on and do the next thing is all anyone can do.

Do any of these actually prohibit alcohol from
Working if you drank on top of taking it? Similar to bupe more strongly binding the same site morphine dose but not agonizing it anywhere near as much thus preventing one from getting high on the drug of abuse?

 

[pcplease]

i mean we have Antabuse as well as Rx Naltrexone or vivitrol specifically for alcohol

ethanols pharmacology isnt nearly as cut and dry as opiods binding to specific receptors. plus just messier all around w/ how GABA works