Most POTENT benzo derivative

[Fertile]

Forget personal experiences, does anyone know of a benzodiazepine that is more potent than brotizolam? AFAIK brotizolam is the only benzodiazepine that comes as 1/8th mg (125 ug) tablets.
As far as I can see, it's optimised for potency but interestingly, it has a triazolo ring which means it has MUCH less a1 affinity. I mean, that's good - less chance of people doing crazy things under the influence but if I recall, nitrobenzodiazepines (even those robbed of a1 activity) are about twice the potency of those with (pseudo)halogens at the 7/8 position (numbering depends on 4th ring being present).

US 4094984 is very specifically for brotizolam so someone had a clear aim in mind.

US4199588A deals with all of the different possible (or at least usual) 8 substituents includes the nitro homologue although it doesn't deal with HOW to make the precursor.
Later patents do NOT mention the 8-nitro homologue. I think the problem is the production of 3-[1-(2-chlorophenyl)ethenyl]-5-nitrothiophen-2-amine. No search brings up the compound.
It IS a total guess but I am reasonably certain that the 8-nitro homologue of brotizolam would be around twice as potent as the parent compound. Once you HAVE that compound, it's reasonably straightforward chemistry to produce the final product. Now, since it's a nitro on an aromatic, a lot of work has gone into their synthesis but it's still something of a sticking point in organic chemistry. If the triazolo is swapped for an imidazolo, it looks like it's possible to increase potency and adding a (chiral) 3 methyl DOES increase activity but I'm not sure if it's increase in affinity or increase in LogP. It's one of the few things I would be reasonably confident about.... but unless your synthesis is chiral, you lose half of your product.


I might add that people may wonder if the o-F homologue is more potent. It is not. It was chosen over related compounds because it's LogP was most appropriate to balance the onset and the duration.

BTW people sometimes imagine that zolazepam must be potent because it's used on elephants... but it's not. It's water-soluble with a short duration of action; THAT is why it was chosen.

 

[Xorkoth]

Flunitrazolam, from what I understand, is recommended to dose at 0.125mg as well, so I think it's probably about the same, though I have no experience with it.

 

[nznity]

Flunitrazolam, from what I understand, is recommended to dose at 0.125mg as well, so I think it's probably about the same, though I have no experience with it.

Holy fk man, 125 ųg... i csnt imagine even touching that shiy.

 

[Xorkoth]

You definitely need to use volumetric dosing... though the same is true of most benzos.

 

[Fertile]

Flunitrazolam, from what I understand, is recommended to dose at 0.125mg as well, so I think it's probably about the same, though I have no experience with it.

Yes - you notice that I actually stated that the 8-nitro homologue of brotizolam might be more potent. Nitrazepam is supposed to be about twice as potent as nordiazepam and the only difference is that the -Cl of nordiazepam has been swapped for an -NO2.

I generally dislike nitrobenzodiazepines because they are a LOT more toxic that all other classes. I don't know why, but I can make an educated guess. I noted that in Sweden, 78% of suicides that involved only benzodiazepines were nitrazepam, flunitrazepam and clonazepam. Diazepam is famously safe in overdose. There was a case in a lab when a worked swallowed the entire supply of diazepam which records showed to be over 4 grams.

We made pynazolam, the 8-nitro homologue of pyrazolam. Now the triazolo ring means it has very little a1 affinity (the subtype Z-drugs bind to) and discovered that the effects were REALLY euphoric. It would seem nitrobenzodiazepines are serotonin releasers (that would explain toxicity) and that is why they are effective hypnotics. It was too damned expensive to make. BUT we did learn one neat thing - a friend who was old enough to have taken Ludes (Methaqualone) said that the closest he could compare pynazolam with WAS methaqualone.

If memory serves we had 2mg tablets made and took 2 each.

 

[negrogesic]

The nitros are potential carcinogens too. Wouldn't think sub-milligram quantities would be problematic but who knows.

Though nitrazolam and brotizolam are more potent by weight, I think flubromazolam is the most "powerful" benzo that is strongly active in the sub-milligram. Nitrazolam and brotizolam are pretty short-acting with fairly weak-moderate muscle relaxant effect. Flubromazolam however is very long lasting, inducing deep hypnosis and powerful muscle relaxation. This makes it far more dangerous in acute overdose. I have sampled flubromazolam but have only ever smoked it (in hopes of making it shorter acting). It still lasts forever. Smoking flubromazolam is like getting hit in the head with a hammer. It vaporizes nicely however.

 

[izo]

from the benzos i know of id say flunitrazepam, a bit more potent than the -lam analogue. brotizolam is a standard triazolo benzo so something like xanax. i have a short list with ki's, in this triazolam is the most potent. but from my knowledge id say flunitrazepam.

gaba-a modulatoren affinität
triazolam 1.31 umol
alprazolam 1.38 umol
clonazepam 1.43 umol
flunitrazepam 1.60 umol
lorazepam 2.65 umol
loprazolam 2.90 umol
lormetazepam 3.58 umol
eszopiclone 4.24 umol
estazolam 4.73 umol
bromazepam 14.61 umol
quazepam 17.06 umol
zaleplon 19.65 umol
zopiclone 21.22 umol
nitrazepam 30.48 umol
diazepam 32.67 umol
medazepam 33.23 umol
nordazepam 33.25 umol
clorazepate 41.27 umol
prazepam 41.56 umol
flurazepam 47.08 umol
halazepam 51.03 umol
ketazolam 53.69 umol
clobazam 59.90 umol
zolpidem 59.90 umol
temazepam 63.90 umol
oxazepam 67.00 umol
chlordiazepoxide 75.00 umol

 

[Fertile]

Values are meaningless without LogP & protein-binding.

 

[simstim]

I miss phenazepam. Phenazepam had everything you could want in a benzo.

It was as potent as alprazolam, cheap, and with a duration like diazepam. Really easy to over do it and black out all day though.

back in the day I took phenazepam everyday for a couple years. Usually just once or twice a day. That's all you need with a half life that long.

 

[Fertile]

Yes - it's slow onset meant a lot of people overdid it and it's long duration means BID will assure a constant plasma level quite quickly.

But it's very unsophisticated. I learnt that you really can design in and out what you want with the 1,4-benzodiazepine scaffold.

Pynazolam taught us al lot i.e. nitrobenzodiazepines are serotonin releasers which I think was unknown. Pyeyzolam showed that alcohol works by how it relatively increases Cl- flow at different subsites i.e. it's action is complex.

But I don't feel most benzos now. I mean, I need 100mg of diazepam to feel anything.

 

[fastandbulbous]

What really got my attention is the fact that thienyldiazepines are much slower at producing dependence, on repeated administration. Etizolam is actually stated to produce better anxiolysis etc after a couple of weeks. Also, the withdrawal is less severe. Add this to the high potency of these drugs and I think they are the most promising area for research (I once made some sterile 2mg/ml etizolam soln in propylene glycol/water. 2mg IMed meant I came around 20 minutes later, on the kitchen floor, wondering what the fuck had happened!)

 

[Fertile]

Ah- no, that isn't because it's a thienyldiazepine but because the 8-substituant is an alkyl group so it has almost no a1 affinity and no a5 affinity whatsoever. However - if you IV it, it's LogP means it will head straight to the brain, so you fall over.

Now the 1,5-benzodiazepines DO seem to cause less dependence although their exact action hasn't been elucidated (as far as I know). Going further afield, etifoxine does not seem to produce much in the way of dependence. The latter is something of a mystery. Almost no QSAR work whatsoever. All I know if that adding a '2-Cl stops all activity.

Overlay them in ChemOffice, it's an interesting exercise.
I think the nitro homologue of brotizolam would be pretty euphoric IF, like nitrobenzodiazepines, it's a serotonin releaser. But that's some complex chemistry. Placing a 2-nitro onto a thiophene ring is interesting. Either simple but you have to separate positional isomers (so preparative chromatography) or you have to form that ring with the nitro in place.

 

[Xorkoth]

Etizolam does seem to take longer to produce tolerance and dependence, for sure. That said, prolonged use, especially in high doses, can still produce horrific withdrawals. A friend of mine would start to approach a seizure after just 6-8 hour without her dose... she was taking 6-8mg every 4 hours at her worst, and for years on end.

Personally I have gone through stages of using etizolam almost every night for weeks/months on end, for sleep (insomnia) and/or drug comedowns, and never caught dependence, though I have gotten to where I had pretty wicked rebound anxiety that took 4-7 days to clear up.

 

[Fertile]

I think that is because it still has a little a1 affinity. I think etizolam (and it's designer homolgoues), pyrazolam & clobazam are the safest of the benzodiazepines. I'm sure if consumed with alcohol one could cause harm, but you would really have to try quite hard.

I think etifoxine can be bought quite legally on the internet. I don't know how UK law would deal with it as it IS a medicine and they are excluded. There could be arguments that it doesn't have a UK licence, but it would get very complex and time consuming. If you were selling and had 20000 in stock... that is a different story.

 

[Xorkoth]

And to think, they recent banned etizolam almost everywhere that it isn't already a prescription drug, but - somehow - decided flubromazolam, of all things, was alright. Possibly the most dangerous benzo yet available. I will never understand the thought process of these people.

 

[Fertile]

And to think, they recent banned etizolam almost everywhere that it isn't already a prescription drug, but - somehow - decided flubromazolam, of all things, was alright. Possibly the most dangerous benzo yet available. I will never understand the thought process of these people.

A very limited understanding of QSAR and Chinese suppliers wanting do make the cheapest product.
IS etifoxine banned? I've not seen it named on any nation's list of controlled drugs. It's action isn't understood and since it has no hypnotic properties, it would be hard to prove it was psychoactive rather than acting on the body in some way. And I mean under UK law, which tries to make anything novel controlled.... and the exception is 'compounds presented as medical products'. So it equates to buying a POM online. Not illegal to order or possess, only illegal to make to sell.

 

[Xorkoth]

It's not banned in the US. Not sure if it is anywhere else. Personally I have never noticed a thing from it.

 

[Conky]

IF, like nitrobenzodiazepines, it's a serotonin releaser..

Care to expand on this a bit more? Was considering Nitrazepam.

 

[Fertile]

Care to expand on this a bit more? Was considering Nitrazepam.

Yes - you must have noted that all of the early hypnotic benzodiazepines were nitrobenzodiazepines? Well that is why. In animal models, they caused sleep BUT their serotonin-releasing properties was never published but then all of those drugs are from the 1960s so I guess people didn't know. Later hypnotics like brotizolam are simply VERY potent. ALL benzodiazepines (and related) are hypnotic at a sufficient dose.

But with pynazolam, it was possible to produce a benzodiazepine with no a1 affinity at all - so we could examine what else the nitro does. We also tried the ethynyl homologue and that is like alcohol. It was an interesting study.

I still think that the 2-nitro homologue of brotizolam is likely to be the most potent benzodiazepine of all. I have not idea if it would have serotonin-releasing properties. The 2-ethynyl is likely to be the most potent alcohol mimic BUT have you seen the synthesis of those compounds? Not friendly.

 

[fastandbulbous]

The era in which the initial hypnotics were introduced, ability to cause euphoria was seen as a good thing. I've always found the nitrobenzos to be like an on/off switch. Great for insomnia, not somuch if just wanting relief from anxiety