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The QSAR of Z-drugs (non-benzodiazepine) GABAa PAMs

Fertile

Fertile

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Mar 31, 2022
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The 3 commonly known 'Z-drugs' are a1 selective hypnotics with a short duration of action but of the 3, Zolpidem has been the most well researched. Indeed necopidem (sedative/anxiolytic), saripidem (sedative/anxiolytic) & alpidem (anxiolytic) all od which received market licences in some nations. They also provide a useful QSAR to define duration and GABAa selectivity.






Structure/activity relationship studies at the benzodiazepine receptor: Pyrido (3,2-b) indoles and annelated 1,4-benzodiazepines as putative BZR ligands - ProQuest

Explore millions of resources from scholarly journals, books, newspapers, videos and more, on the ProQuest Platform.
www.proquest.com www.proquest.com

The key to producing one of these compounds as an RC is the complexity of the synthesis, the cost of the initial precursors and the potency of the final product.

Possibly the most interesting is the research compound pagoclone. While working with Professor Nutt I was able to acquire a sample of pagoclone ant it certainly has alcohol-like activity. But it's dose-response curve means that past a certain (quite low) dose, the response curve plateaus and so while it's excellent at emulating 2 glasses of wine, it has no effect beyond that point. Still there are patents showing that the structure giving partial a1,a3,a4 & a5 activity can be altered for produce pure PAMs i.e. an RC that will make the user 'fall over' drunk... without actually falling over, throwing up, suffer fluctuating mood or amnesia... the negative effects associated with alcohol.

I'm going to sit down and find and link to every patent that refers to these non-benzodiazepine anxiolytic/hypnotic compounds.

While it's arguable as to the reach of the DEAs scheduling of certain benzodiazepines as schedule 1 and what that means. Sooner or later producers are going to require a compound as active as bromazolam (for example) but isn't under any legal control.

So please bare with me. This is going to take many weeks.
 
Fertile said:
The 3 commonly known 'Z-drugs' are a1 selective hypnotics with a short duration of action but of the 3, Zolpidem has been the most well researched. Indeed necopidem (sedative/anxiolytic), saripidem (sedative/anxiolytic) & alpidem (anxiolytic) all od which received market licences in some nations. They also provide a useful QSAR to define duration and GABAa selectivity.






Structure/activity relationship studies at the benzodiazepine receptor: Pyrido (3,2-b) indoles and annelated 1,4-benzodiazepines as putative BZR ligands - ProQuest

Explore millions of resources from scholarly journals, books, newspapers, videos and more, on the ProQuest Platform.
www.proquest.com www.proquest.com

The key to producing one of these compounds as an RC is the complexity of the synthesis, the cost of the initial precursors and the potency of the final product.

Possibly the most interesting is the research compound pagoclone. While working with Professor Nutt I was able to acquire a sample of pagoclone ant it certainly has alcohol-like activity. But it's dose-response curve means that past a certain (quite low) dose, the response curve plateaus and so while it's excellent at emulating 2 glasses of wine, it has no effect beyond that point. Still there are patents showing that the structure giving partial a1,a3,a4 & a5 activity can be altered for produce pure PAMs i.e. an RC that will make the user 'fall over' drunk... without actually falling over, throwing up, suffer fluctuating mood or amnesia... the negative effects associated with alcohol.

I'm going to sit down and find and link to every patent that refers to these non-benzodiazepine anxiolytic/hypnotic compounds.

While it's arguable as to the reach of the DEAs scheduling of certain benzodiazepines as schedule 1 and what that means. Sooner or later producers are going to require a compound as active as bromazolam (for example) but isn't under any legal control.

So please bare with me. This is going to take many weeks.
Click to expand...

Maybe there is potential for developing a beta-carboline based GABAergic with BZD site affinity like abecarnil 🤔. Would legally benefit from the fact that it isn't related to controlled substances like pagoclone. How enjoyable the effects are, who knows.
 
I think abecarnil iself it worth QSAR studies.

But the fact remains that benzodiazpines - someone's 'golden goose' is going to get slaughtered.
I mean we have a perfectly good legal cocaine alternative (which QSAR shows can be improved) BUT it's going to need someone to figure out that cocaine (the last natural drug for which their is no alternative) can be replaced and as I suspect with benzodiazepines - too many people have a job relying on that fact.

Amazing (to me) that these enterprises build up but not one person involved has ANY reason to say you know what - we can make this at a tenth of the price.

So benzos and those just manipulating known scaffolds are in for a shock. Someone will turn up offering alternatives. OK it might take w while to convince people but my experience (with pyrazolam and others) is that you only need yo give 200 people free samples... and you have 5000 converted who go on to convert 50,000 people, a million and so on.

It's not like I have dropped a totally novel compound into circulation. ANYONE conversant in QSAR will understand.
There are also many ways to sell the product - even in shops. Anyone recall 'Sleeping Buddha' or the original 'Spice'? It took 5 years for people to find the active'? If your active is actually LEGAL then it could last a decade or more!
 
Last edited:
www.sciencedirect.com

Probing the molecular basis for affinity/potency- and efficacy-based subtype-selectivity exhibited by benzodiazepine-site modulators at GABAA receptors

The extracellular α(+)/γ2(−) interface in the α1,2,3,5βγ2 GABAA receptor harbours the allosteric binding site targeted by benzodiazepines and newer ge…
www.sciencedirect.com www.sciencedirect.com

www.sciencedirect.com

Subtle Changes in Residue 77 of the γ Subunit of α1β2γ2 GABAA Receptors Drastically Alter the Affinity for Ligands of the Benzodiazepine Binding Site

Recombinant α1β2γ2 γ-aminobutyric acid type A (GABAA) receptors were functionally expressed in Xenopus oocytes. Upon the mutation F77L, diazepam and R…
www.sciencedirect.com www.sciencedirect.com

https://www.mdpi.com/1422-0067/21/1/334 - useful overlay
I've initially investigated the 4-phenylimidazo[1,2-a]pyridin-3-yl]acetamide class of agent to see if it's possible to produce less selective ligands. Alteration of the duration of action of this class proved to be trivial. You will note that in all cases a tertiary amide function is present at the 3 position of the system.

Interestingly the ester may be reversed suggesting that it is the electronic character rather than specific space-filling that is important. Pubchem reveals that literally hundreds of homologs were produced.

Note that the 4 & 6 position generally require a space-filling moiety (those not amenable to metabolism show significantly longer duration). The presence of the 4 substitution appears to increase subtype selectivity; a number of examples lend weight to this concerpt.

The alkyl substitution of the amide function is also responsible for GABA the subtype selectivity. With the Z-drugs seemingly able to bind to subtypes inaccessible most classes of benzodiazepine (but not some of those used experimentally).

Below is a selection of the 4-phenylimidazo[1,2-a]pyridin-3-yl]acetamide class anxiolytic/hypnotic medicines which begins to unravelled the QSAR of this class:

https://ibb.co/0F4rDFk

But the KEY thing about any novel agent is it's synthetic complexity (i.e. can it be made cheaply and easily)

ibb.co

2 hosted at ImgBB

Image 2 hosted in ImgBB
ibb.co ibb.co

As you can see from above. the 4-phenylimidazo[1,2-a]pyridin-3-yl]acetamide class can be made from 2 commercially available materials.
 
BTW right now benzodiazepines are worth $5 million/Kg so I fully expect organized crime to be running things.

It's going to get nasty. We are seeing pilling plants being busted and people being arrested. I don't think violence can be far away.

I mean - people are being stabbed and shot over $10 deals of H so why should this be any different?
 
I told people this when things were legal but btc required. Not a one person had enough fath in me. oh yea i was gunna pay up front too. bah.
 
I do not trust anywhere that will not accept credit cards. If you are providing compounds that are totally legal, why would you feel the need to hide so damned much?

Not that I think bitcoin is anywhere nearly as good at hiding people as they seem to think. I mean, people follow wallets and ultimately while you can convert money INTO bitcoin, you cannot convert it back out. VERY few legitimate businesses accept crypto because of a multitude of problems. Fees for cashing out, variation it it's value...

An ultimately that it's worthless. The only reason people get into crypto is GREED. They are simply hoping to find someone even more greedy who will pay even more. It's a non-yielding asset. Buy a business and it produces goods and/or services. Bitcoins do not produce MORE bitcoins.

I note that FUD seems to be cryptospeak for 'woke;. Yeah, I woke up and realized that crypto is a bubble. History is littered with them.
 
The idazopyridine scaffold is the most amenable to altering selectivity and duration. From the examples I have given, it's possible to make all of the compounds I listed in 2 steps from commercially available intermediates.

What is also a bonus is that since nobody can use Reaxys of Pubchem to find the novel versions of the compound, they won't know what they are making.

Such compounds will be active at around the 6-10mg dose range but given how much people are prepared to pay for 'benzo-like' compounds, that still represents a REALLY stupid profit margin. I honestly think people are making the strongest compounds possible merely because they calculate immense profits... but if you can expect to make 1000% profit on a LEGAL compound, I can only see unlimited greed leading to people choosing dangerous, untested compounds.

At least the ones I'm considering have been through animal trials (and all of the tests that come BEFORE animal testing.

Since potent benzos now come in solution, I've even worked out prodrugs that are themselves inactive... until you boil them in water for an hour! That means the end user is actually the one producing the active. It's the belt-and-braces approach.

BTW there are likewise prodrugs for benzofuran, MDA, amphetamine, K (and MXE) and even some (novel) opioids.

If you supply someone with a totally inactive compound and THEY go on to modify it, I imagine that until said prodrugs are legally controlled, the seller is breaking no laws.
 
negrogesic said:
Maybe there is potential for developing a beta-carboline based GABAergic with BZD site affinity like abecarnil 🤔. Would legally benefit from the fact that it isn't related to controlled substances like pagoclone. How enjoyable the effects are, who knows.
Click to expand...

BTW yes there is most certainly room for research into the beta carbolines with abecarnil being a good prototype.

The isopropyl ester appears to be space-filling although at this stage the isopropyl is most favoured. Derivatives with ring-substitution of the 6-benzoyloxy are known, but no activity data appears to be extant.

That is why I chose the zolpidem derivatives. Research dates back to the 1980s and their are sufficient examples with sufficient development for someone to begin work on a QSAR.

You wait - when the benzodiazepines are controlled, it will be zolpidem derivatives that take over. It seems you can make them less selective as well AND a bit more potent. I mean, I guess if people would like a less-sedating, longer-actining zolpidem derivative, their will be a market. Both R1 & R2 represent sacrificial moieties i.e. part (or even ALL) of their function is to provide the body with a way to metabolize them AND they also seem to mediate selectivity.

I'm confident that it's possible to entirely mimic the benzodiazepine class with the imidazopyridine class. Interesting that space-filling seems to be key. Only alkyls are used but it makes me wonder if alkynyl and halogen groups (often found in sedative hypnotics) will be introduced. I mean, if nothing else they introduce non-rotatable bonds and increase rigidity - both associated with increased potency.

But right now someone needs to approach a Chinese or Indian manufacturer of Zolpidem to ask how much the analogues would cost to produce. In both nations the entire class lacks any legal controls.
 
Fertile said:
BTW yes there is most certainly room for research into the beta carbolines with abecarnil being a good prototype.

The isopropyl ester appears to be space-filling although at this stage the isopropyl is most favoured. Derivatives with ring-substitution of the 6-benzoyloxy are known, but no activity data appears to be extant.

That is why I chose the zolpidem derivatives. Research dates back to the 1980s and their are sufficient examples with sufficient development for someone to begin work on a QSAR.

You wait - when the benzodiazepines are controlled, it will be zolpidem derivatives that take over. It seems you can make them less selective as well AND a bit more potent. I mean, I guess if people would like a less-sedating, longer-actining zolpidem derivative, their will be a market. Both R1 & R2 represent sacrificial moieties i.e. part (or even ALL) of their function is to provide the body with a way to metabolize them AND they also seem to mediate selectivity.

I'm confident that it's possible to entirely mimic the benzodiazepine class with the imidazopyridine class. Interesting that space-filling seems to be key. Only alkyls are used but it makes me wonder if alkynyl and halogen groups (often found in sedative hypnotics) will be introduced. I mean, if nothing else they introduce non-rotatable bonds and increase rigidity - both associated with increased potency.

But right now someone needs to approach a Chinese or Indian manufacturer of Zolpidem to ask how much the analogues would cost to produce. In both nations the entire class lacks any legal controls.
Click to expand...

I know you were referring to derivatives but out of curiosity I asked that ai chatbot the binding values of abecarnil and it came up with:

"According to a study published in the Journal of Pharmacology and Experimental Therapeutics, the binding affinity of abecarnil for the different BZD receptor subtypes is as follows:

α1 subtype: Ki = 0.56 nM
α2 subtype: Ki = 3.1 nM
α3 subtype: Ki = 4.4 nM"

By contrast it gave me the following for zolpidem:

α1 subtype: Ki = 2.2 nM
α2 subtype: Ki = ~22nM
α3 subtype: Ki = ~155nM


So it looks like abecarnil is a little less selective than zolpidem for a1 relative to a2 (and alot less selective relative to a3).

Personally I used to find zolpidem enjoyable, but its not a great drug for the average person due to the intense hypnotic and psychotomimetic effects at higher doses.
 
Butt accuracy is app.

People will GIVE me neuroleptics with such action.

We want accuracy.
 
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