Pyeyzolam - better than ethanol

[clubcard]

https://image.ibb.co/fXkdBm/pyeyzolam.png

8-ethynyl-1-methyl-6-(pyridn-2-yl)-4H-[1,2,4]triazolo[4,3-a][1,4 benzodiazepine

Another variant of the pydinodiazepine scaffold.

3mg = 1 unit (10mL) of 100$ ethanol.

It proved that the positive effects of alcohol (relaxation, euphoria,hypnotic) from the negative effects (ataxia, aggression, nausea, diuretic, amnesia). From a cohort of 103, the dose/response wasn't altered by body-weight and the drug wasn't metabolized; excreted unchanged. QI-II-66 lasts too long. The T1/2 of this was 280 minutes ? 22 minutes.

After initial trials, a small cohort (N=7) proved that dependent alcohol users found that it totally prevented abstinence syndrome. We were looking into the addition of 1-amino-cyclopropanol, (AOD inhibitor) to prevent concomitant use of alcohol.

So, it all works well but to treat alcoholics, too much work for a license. As an ethanol replacement, going against a $7 billion industry meant impossible to license. That >250,000 people die from the results of ethanol clearly doesn't make it a product that no government has worked out. David Nutt & Dr. Dave have the lab-notes

The synthesis is somewhat problematic but a dare say a chemical engineer would find a route in which the -Br --->-C☰CH would make it cheap. I mean under 40p per dose unit. So even with tax and duty, if solutions were put into soft drinks, the price would match that of alcohol. That is the most important thing. Powder, while having a massive TI, can result in a 'missing weekend' (hypnotic), it is also a date-rape drug so only licensed formats would make it practical and safe for people.

Never design a drug you aren't willing to take yourself as the fist in-man. I caned an awful lot of it but I wouldn't recommend it. I have come close to paying the price, but someone has tol

 

[Weltmeister]

A benzodiazepine without memory impairment ? That sounds too good to be true.

 

[clubcard]

A benzodiazepine without memory impairment ? That sounds too good to be true.

Well, it turns out that seemingly all of the negatives of alcohol are mediated by it's NMDA activity. Of course, we started with QI-II-66 which was qualitatively the same apart for it's long duration and of course, novel metabolites. Then we just applied the same 7 (8 on the four-ring benzos) position moiety because we knew that the body couldn't metabolize pydinodiazepine. The reason we went with the pydinodiazepines was because the ADME was so good. Not as lipophilic (the -N=) as the (substituted) benzene but had a higher affinity.

This is just the one that I hope some people here will have already tried and thus can post their own experiences. I can't see the Chinese being able to make this one. It took 4 people six weeks to find A route, but not a GOOD route. preparative chromatography is a dark-art in it's own light. Those who failed to follow the 6ps when walking into the work will know what I mean.

This isn't the 'best in class' but we used rational design to find the range of selectivity we could derive derive from it. I consider this to be of great benefit because people with great reputations have quietly stored the study data so hopefully we will eventually find a place for this class. We also derived work from Upjohn and Jack's work on novel antidepressants was carried out via a mutual friend slipping us the lab notes.

 

[Weltmeister]

Well the memory impairment of benzodiazepines is at least partly mediated through the α5-subunit. Unfortunately this the exact subunit that QI-II-66 and (going by your description) Pyeyzolam are selective for. Isnt it reasonable to assume that theyll have similar memory impairment to all the other benzodiazepines ?

What im trying to understand is why this benzo is supposed be superior to other benzos to treat alcoholism.

sorry for being so critical.

 

[clubcard]

Well the memory impairment of benzodiazepines is at least partly mediated through the α5-subunit. Unfortunately this the exact subunit that QI-II-66 and (going by your description) Pyeyzolam are selective for. Isnt it reasonable to assume that theyll have similar memory impairment to all the other benzodiazepines ?

What im trying to understand is why this benzo is supposed be superior to other benzos to treat alcoholism.

sorry for being so critical.

Not at all. I should have qualified that the memory loss only occurs at 'heroic' doses. Once again, we managed to obtain new data. It is a far better medication than other drugs (clomethiazole being the only decent alternative) is because it is selective. The problem with other benzos is that for someone dependent on ≥40 units of alcohol per day (for example), a sufficient dose to prevent abstinence syndrome would be far, far too hypnotic AND if you give an appropriate dose of any other benzodiazepine, you are building up tolerance and dependence at 3 more receptor subtypes (at least).

I'm pretty sure some people on here tried out the stuff; circa 180,000 dose-units walked off with the project manager and I don't think that they just threw it away. I could write down my experiences but I could be biased; I could be downright lying. I have no practical way to prove anything but if people take the extant data on QI-II-66 then apply Chemoffice tools for physical properties, there is at least physical data that will give some credence of activity.


People on eunoiapharmacopia will certainly know all about it; they certainly gave a lot of positive reports.

 

[Weltmeister]

Its blatantly obvious that youre lightyears ahead of me. If i ever come across it ill make sure to report my experience itt.

Coming from an area where ~25% of people have an alcohol problem i have nothing but respect for your work and hope you succeed.

 

[clubcard]

Its blatantly obvious that youre lightyears ahead of me. If i ever come across it ill make sure to report my experience itt.

Coming from an area where ~25% of people have an alcohol problem i have nothing but respect for your work and hope you succeed.

Well, Weltmeister in all honestly one of the main reasons I wanted this in the public domain was to help people who are dependent on alcohol. We confirmed that is solely the α5 affinity that causes alcohol dependence (good for all researchers to know) but just as importantly, it is the NMDA activity responsible for the negative effects. The euphoria implicates the α5 subtype with dopamine release. Compared with the parent compound, pyrazolam, an anxiolytic with virtually no euphoria leaves only the action of α1 subtype officially connected with alcohol. The Z-drugs are α1 selective so we can further state that the hypnotic effects of alcohol are mediated by this site.

We never tried making any other tricyclic or tertacyclic analogues but only the duration differed when compared to QI-II-66. It is reasonable to suggest that diazepam and alprazolam will act as direct precursors to similarly selective derivatives. We tried all of the halogens, pseudohalogens and just about every EWG we could apply to that 8 position. The reason we went with the almost untried pyridinyl homologues was primarily because it's ADME is predictable (lose the M!) and because it was patentable.

It would be of great interest to me to see the activity of the 7-ethynyl analogue of clobazam (or tetracyclic derivative). That could prove to be fertile ground. For the last step of the 'i wish' list would be the etifoxine analogue. If you overlay the 3 structures in Chemoffice, I'm sure you will note the VERY similar aromatic, lone-pairs and EWGs are. While the patents noted that the '2-chloro analogue of etifoxine was less potent and more toxic, the pyridine ring may provide further activity for the class. I do hope people will take a look and see. That is all I did; nothing clever, obviously.



"The step from the laboratory to the patient's bedside is extraordinarily arduous and fraught with danger." - Paul Ehrlich

 

[Weltmeister]

Sorry but I have to contradict you here. Pyrazolam is definitely euphoric. One of my most experiences euphoric experiences ever was a direct result of ingesting 2mg of pyrazolam (0 tolerance). Whenever i take lower doses i also find it quite enjoyable.

A friend of mine also reported quite prominent euphoria from 0.5mg of pyrazolam.

Ive also read a few forum posts of people saying they get eupohria from it. Just seems to be a lower percentage than for other benzos.

Benzos are quite strange compounds. Some get immense pleasure from them and others none at all.

 

[clubcard]

Sorry but I have to contradict you here. Pyrazolam is definitely euphoric. One of my most experiences euphoric experiences ever was a direct result of ingesting 2mg of pyrazolam (0 tolerance). Whenever i take lower doses i also find it quite enjoyable.

A friend of mine also reported quite prominent euphoria from 0.5mg of pyrazolam.

Ive also read a few forum posts of people saying they get eupohria from it. Just seems to be a lower percentage than for other benzos.

Benzos are quite strange compounds. Some get immense pleasure from them and others none at all.

This is BAD news. The whole point of pyrazolam was to be a less abusable anxiolytic. Of course, the dose was intended to be 0.5-1.0 mg [QID] maximum for a maximum of 14 days. That one we DID get into proper trials and the animal models at that dose didn't form dependence (I'm including both physical and psychological). Well, I guess we live in a world where people abuse the Z drugs & the GABA analogues.... both of which don't seem popular with animals so you never can tell.

 

[Weltmeister]

Dont get me wrong i love pyrazolam. It has much less memory impairment, is much less hypnotic and seems to produce less respiratory depression when mixed with other depressants. Its probably the best anxiolytic benzo available right now.

Also if less people abuse pyrazolam compared to other benzos wouldnt that already be a success ?

 

[clubcard]

Dont get me wrong i love pyrazolam. It has much less memory impairment, is much less hypnotic and seems to produce less respiratory depression when mixed with other depressants. Its probably the best anxiolytic benzo available right now.

Also if less people abuse pyrazolam compared to other benzos wouldnt that already be a success ?

Well, I have no idea about the market. The research group were just finding novel ligands based on the Upjohn work. It was just a scaffold with nice (i.e. no) metabolites that was water-soluble (sublingual films) and was amenable to subtype selectivity. I just posted because I've seen a few people I know die from excessive alcohol (ab)use. It is the way of medicinal chemistry. Nobody will put the money in if they don't feel that their is a chance of being successful, block-busters in fact. An alcohol mimic that directly substitutes means if nothing else, we know just what alcohol dependence is and what activity was mediated by what receptors. That it was so clear cut was actually a surprise. All manner of activity has been studied but just 1 subtype is responsible for the desired effects.

I suppose I would be pleased if it did end up replacing alcohol (that's 2.5 million people dying per annum saved) and was controlled and taxed like alcohol. I'm a firm proponent of informed choice, but so many novel compounds, so little research. I'm pretty sure we were the only ones working with Huntingdon Life Sciences. The 3Rs and quite.... bold FIM studies.

 

[Weltmeister]

Well maybe itll appear on the RC scene after the next banwave. Without a good route to synthesis i kinda doubt it though.

 

[clubcard]

The immediate precursor is pyrazolam but I think we had to try about 24 different solvents before reaching one that gave a molar yield of about 74-76%. Don't forget, losing the -Br means a lower MW.

 

[Weltmeister]

I suspect that the profit margins on these are so high that losing a portion doesnt really matter that much. Still very much worth it if it has the potential to become a highly sought out compound

 

[markosheehan]

Cool post.

Do you have the binding info for this substance at the gabaa subunits?

I do not see why this would be better than other benzos that hit alpha 5 subunit aswell and all the negatives it brings. Would it cause the same brain function impairment as regular benzos?

 

[clubcard]

Cool post.

Do you have the binding info for this substance at the gabaa subunits?

I do not see why this would be better than other benzos that hit alpha 5 subunit aswell and all the negatives it brings. Would it cause the same brain function impairment as regular benzos?

HLS provided the affinity data. It was around 2.1+-0.3 at the α5 subunit being a couple of orders less active at the other diazepam-sensitive sites. You might expect more activity given that value but the LogP isn't quite as high as pyrazolam. Being more water-soluble is what makes the kinetics more alcohol-like. The subjective effects are because of the big difference of Cl- ions passing through one sub-unit compared to the others. That is an interesting find. That end-stage alcoholics found it totally substituted is evidence that alcohol-dependence is mediated by that one subunit. We began looking at the Z-drugs in animal models to see how important the α1 subunit affinity was in it's contribution to subjective effects of alcohol. Almost nothing, as it turned out, the ataxia, hypnotic and other negatives. Another interesting find.

Non dependent users (and I know some people here were part of the cohort) found the effects to mimic the positive effects of alcohol without the negatives. We didn't find a single one who wouldn't be prepared to take part in a future trial which we took as a very hopeful sign. Of course, skepticism is the default state but it was a commercial rather than medical issue that ended the work. The pyridinyl benzodiazepines do solve several other problems but a Canadian university had already made and patented them by structure, not action so we did feel a bit hard done by not to at least be able to publish. I've sat out the 5 year NDA so now I can at least give some data; but not the detailed synthesis which wasn't my work and wasn't even done in my nation.

Dr Nutt is working with a team on another alcohol alternative. We did actually look at several of the partial agonists he discussed some years ago. Pagoclone along with QI-II-66 were also tested but in animal models the former failed to substitute and the latter had a quite tremendous T1/2. Rats liked the former but people not as much. The latter substituted for alcohol in drunken mice and helped with alcohol dependent people BUT wasn't that pleasant. Another part of alcohols euphoric effects is the dynamic increase in Cl- ions through the α5 subunit. Another interesting find.

Finding out why alcohol is pleasant was about the most important outcome. I suspect that being a full agonist and obviously producing such good outcomes in trials damned it. Used in medicine it is too abusable, used as an alcohol replacement it may prove to be more dependence forming). We didn't reach the second batch of animal testing to see how re-enforcing it was but in all likelihood, it was very likely to be more dependence forming because of the lack of any negative re-enforcement (hangover). If you can get blind drunk every night and be fine next morning, the ability to just repeat the experience is more likely. I think Dr Nutt has quietly thought it through and has gone for something that has a ceiling effect.

Still, I don't see this turning up considering the alternatives.

I think it's about 2 months until the other stand out member of the class passes the 5 year mark.

 

[markosheehan]

what is Nutt going ahead with do you know? do you know when it will be made available?



this is from wiki "Recent research has produced several ligands which are moderately selective for GABA_A receptors containing the α₅ subunit. These have proved to be useful in investigating some of the side effects of benzodiazepine and nonbenzodiazepine drugs, particularly the effects on learning and memory such as anterograde amnesia. Inverse agonists at this subunit have nootropic effects and may be useful for the treatment of cognitive disorders such as Alzheimer's disease."

so should scientists not be looking for substances that act as inverse agonists at this site instead of agonists that cause these harmful "side effects". ? .the whole point of alcosynth I thought was to find something similar to alcohol without the negatives, and not producing a compound with some of the same negatives.

 

[clubcard]

what is Nutt going ahead with do you know? do you know when it will be made available?



this is from wiki "Recent research has produced several ligands which are moderately selective for GABA_A receptors containing the α₅ subunit. These have proved to be useful in investigating some of the side effects of benzodiazepine and nonbenzodiazepine drugs, particularly the effects on learning and memory such as anterograde amnesia. Inverse agonists at this subunit have nootropic effects and may be useful for the treatment of cognitive disorders such as Alzheimer's disease."

so should scientists not be looking for substances that act as inverse agonists at this site instead of agonists that cause these harmful "side effects". ? .the whole point of alcosynth I thought was to find something similar to alcohol without the negatives, and not producing a compound with some of the same negatives.

As I understand it, Dr. Nutt has moved on from the pagoclone class to something that can acquire a patent. What that is exactly I don't know because it has yet to be patented. Someone with the funds to replace ethanol would need billions, not the millions we had. It is important to note that the 1,4-benzodiazepines bind at the αxβ1 (where x is 1,2,3 and 5) junction. The 1,5s bind at the αxβ2 (where x is 1,2,3 and 5) and the benzooxazinamines at the αxβ3 (x = don't have QSAR) so pyeyzolam is very selective indeed. I think I mentioned that the 1,5-benzo would be interesting and someone following up on the Etifoxine derivatives patented for alcohol withdrawal. I think that is where people get a little confused. We were able to leverage a lot of data from a few dozen compounds.

It may well be that a partial agonist at the α5βx (where x = 1,2 & 3) would also emulate the subjective effects without being so dependence forming. Dr. Nutt is a very clever man but he is also a realist. He did get some of our results and was thankful but looking at making an alcohol replacement, something that LOOKS like any other benzo when drawn as a 2D image is going to run into problems with the press and indeed with the medical establishment. I can guess at the rough structure. I will have a minimum or near-minimum energy state that provides affinity to the α5β1 & α5β2 and possibly α5β3 subunits. If you overlay the three classes I mentioned you will see that it is the angle of the 6 (or 7 if 4 ring) aryl group relative to the benzodiazepine system. Something with some flexibility at that point of the scaffold would work. Of course, then the affinity would be awful. A non-classical pentavalent bioisostere in which VESPR allows interconvention between 2 or maybe 3 near-minimum energy active conformations would work. That is easier said than done. QI-II-66 or the '2 chloro derivative would yield a long-acting non-toxic replacement to help the alcohol dependent (but it isn't going to happen) and at least an intermediate substitute until the stuff is perfected (but it isn't going to happen) to stop the 2.5 million deaths per annum would be pragmatic.

What can I say. We did find something that worked very well. It lengthened the lives of at least a few people but just because of that, it isn't a certainty to be acceptable or profitable to government and business.

 

[clubcard]

BTW the ethynyl group is a hydrogen bond donor and the nitrogen in the pyridine is a hydrogen bond acceptor so along with the established 7 (or 8 in 4-rings) -NO2 moiety, it more as likely act in a manner unknown to all other compounds in the class. Clearly the nitro increases α1 affinity but not so the ethynyl. When I think back, I can remember people being excited to elucidate the activity displayed by novel ligands. A 7-ethynyl homologue of clobazam may well be a great series to study. 4-ring derivatives are known but no o-pyridinyl derivatives so I expect could be patented, but will it likewise be alcohol-like.

BTW if you swap the 8-ethynyl for an 8-trifluoromethyl, you get a selective α1β1 ligand. That was why we went with the synthetically complex pyridinyl benzodiazepines. Halogens, pseudohalogens, alkynes and other groups gave us access to very selective agents. While Ro15-4513 might look like a good idea on paper, paper is the place to leave it. Azides are something rarely encountered in medicine because of possible mutagenic, teratogenic or other long-term issues. Of course, as a species it isn't much fun to be around...

Oh - and the 4 position (AKA 3 position in simpler, tricyclic benzos) is interesting. If you want to make a very high-affinity tricyclic analogue with a short T?, adding a 3-methyl reduces the fludiazepam homologue is an example of fast in, on and out. It is oxidation fodder.

 

[clubcard]

Journal 6751, GB1813962.6, Applicant: Alcarelle Holdings Limited Title: Mood enhancing compounds. Date Lodged: 28 August 2018

Inventors are listed as David Nutt and someone else. Well, I'm not David Nutt.