Pharmacology Barbiturate toxicity; Barbiturate derivatives; Relationships between derivatives

[Flynnal]

Finally had time to upload these to some hosting server, they are the standard portable document file (PDF) format and most anyone can read them.

These are in the public domain and have been since 2009-2010, but they disappeared for some unknown reason and I could no longer find them online, however I did keep copies. These are detailed about barbiturate toxicity, and about the various barbiturate derivatives, a very brief mention of the history of these drugs and some of their forms (ie. pentobarbital, amobarbital, etc) are mentioned. I think the first document describes 7 different barbiturate drugs. The second one shows a list of a fairly reasonable number of different barbs, complete with colour-coded information about potency, onset, duration, etc. The third one is the most interesting of all, as it describes the side chains of many different barbs, and there is a derivation tree, but according to the author the marketing of the drugs over the years isn't relevant to the derivations. I suppose it's because whoever wrote this was dealing with chemical relations as opposed to when they were marketed.

All in all, very fascinating to read these.

https://www.mediafire.com/file/ljenfca899gdd71/finale_05_2009_novembre_jour16_anglais.pdf/file

https://www.mediafire.com/file/cgsz38f8p0jbf40/finale_06_2009_novembre_jour27_anglais.pdf/file

https://www.mediafire.com/file/4t2z70wq5xvl3ai/finale_07_2009_decembre_jour21_anglais.pdf/file

Enjoy reading them. I know I did. Very fascinating, even if it didn't answer every question I had. Not sure whether the colour coded info about the different barbs on the 2nd one has any relation to barb SARs, but it is very interesting to see the largest size of the side chains (especially the 2nd chain) having teh highest potency, but surprisingly there isn't that much connection between durability of activity and the side chains. It seems to be a random thing. Bizarre indeed. Applied chemistry and forensic toxicology dude wrote all these in 2009. My guess is the dude didn't have all information to create a really good SAR calculator, but he provided enough infos to help understand most of the common barbs.

 

[3DQSAR]

Dozens of barbiturates have been well studied and as a class of drug they lend themselves almost perfectly for use as a training set.

 

[Flynnal]

Dozens of barbiturates have been well studied and as a class of drug they lend themselves almost perfectly for use as a training set.

Indeed they are almost perfect for the purpose of academic training. I've been searching for this dude but can't find him anywhere online. But I did keep a copy of these files, because they really provided a nice bit of info on the different ones. I've never done talbutal, that's supposedly even more potent than Seconal and that would make it the most potent one outside of the anaesthetics. But talbutal is less toxic than secobarbital going by the key so I can only presume that potency doesn't have as much to do with toxicity as one would assume. Amytal is supposed to be more potent than Nembutal too, but it has a slower onset of action and is more durable, as well as being less toxic than Nembutal, which is what prompted me to do some more delving on these drugs. They fascinated me, but at the same time they also confused me. I've done a few, and the one that stood out for me was vinylbital, it has the edge over Nembutal as far as potency goes, but not in a nice way, more in a dizzy and nauseating way. It's not the party drug that Seconal is, but it has much the same kick-in.

It's strange that I took 300mg of Nembutal and felt a bit dizzy. Did the same with Neur-amyl (which is just Amytal) and slept for a few hours more than usual. Took 300mg of vinylbital and was dizzy and throwing up after almost passing out. So I absolutely believe whatever the author was saying about its toxicity and I learned the hard way not to mess with this stuff. It really stands out in that regard. When I first knew about it I thought it was just this average barb like butalbital or phenobarbital, but I got a rude surprise when I actually tried it. It hit like a freight train too. I started to feel its effects in very short order, certainly a long time before I felt the Amytal (which is something it seems to be compared to). That said, Amytal was damned potent and really hammered me down, but I just never got really dizzy or threw up. 100mg of vinylbital pretty much assured a solid 6 to 8 hours of sleep - not the best sleep quality, but if you were desperate, it did the trick.

 

[3DQSAR]

Are the links you provide to papers you have obtained from journals? I'm not complaining, but if there are titles and better still DOIs then it's possible to obtain them via institutional access.

BTW when studying the various barbiturates, I think it important to read the patents. It's often the case that competing manufacturers will always seek to provide a 'novel' compound i.e. one that can be patented. So quite often they choose a sub-optimal medicine because they CAN obtain a patent.

 

[Flynnal]

Are the links you provide to papers you have obtained from journals? I'm not complaining, but if there are titles and better still DOIs then it's possible to obtain them via institutional access.

BTW when studying the various barbiturates, I think it important to read the patents. It's often the case that competing manufacturers will always seek to provide a 'novel' compound i.e. one that can be patented. So quite often they choose a sub-optimal medicine because they CAN obtain a patent.

I found them in March/April 2010 and have no recollection as to where they were actually from. My memory is about as sharp as playdoh, so I can't answer that question. The links are just temp links I uploaded the docs to because I was unable to find their source.

 

[3DQSAR]

Oh, I know THAT feeling.

I note that the QSAR of the barbiturates now appears to be a very common 'introduction to QSAR' in post-graduate Medicinal Chemistry courses.

I remain to be convinced that simply counting the total number of carbons of the 5.5 disubstitution is in itself telling one much. I suspect it's simply showing people strategies to FINDING patterns. I mean, they don't go on to explain why aromatic rings and alkenes MAY further explain activity because they have pi bonds. Going further, they carefully avoid covering examples with alkynyl moieties or halogens (well, specifically bromines).

If I were really intent on understanding the QSAR I would find a general route to make glutethimide analogues since then if the disubstitution is asymmetric, the analogues are chiral and we KNOW that the two isomers of glutethimide have significantly different properties.

Obviously the synthesis used to produce glutethimide isn't general enough to produce the analogues BUT one could consider that as a decent part of the research. The side www.drugfuture/com will list the name of the original patent but since glutethimide did become a commercial product. it's possible that someone found and published a better route.

FYI long ago I looked at that patent and noted that the named inventor(s) (I forget if it was a plural) didn't appear to do anything related before or afterwards. If I was asked to guess, I would suggest that the producers just wanted a quick and dirty patentable barbiturate alternative and it would make sense to begin with the 3-phenyl-3-ethyl as the FIRST target. That worked and they just moved on.

A guess, but I've known enough about the development of some other medicines to know classes that were carefully researched and those that were sort of knocked out quickly because the management wanted a 'me too' drug ASAP. Glutethimide has all the hallmarks of a 'me too'.

 

[Flynnal]

Revisit the thread, my memory gotten facelift especially for old stuff in past. So, okay, now recall labels on bottles, both of bottles, before they mistakenly discarded 2015. They sit in landfill I mourn there absence in this knowledge that I really want to end my life if can no longer enjoy music because this stupid chronic inner ear disease or whatever. These would have taken great care of this problem without trouble. IF STILL HAD THEM!!!

One pentobarbital sodium, common everywhere, remember "57-33-0", of course, but forget how much powdered Nembutal in bottle, but nearly 6g and probably cause death on its own not ever touching vinylbarbital too. Clear plastic bottle, labels on both of plain blue on white. Lot of chinese characters. You'd feel ripped off of if you had there for any other reason than for self-destruction (and for that the quantities would is both sufficient and so priceless thing to have if you wanted to die at peace), both had had 25g in them but amounts received far less. A much far less. I did not care. I wanted them this purpose. The other bottle identical but different name. Both "POISON" print on both and again a lots of chinese characters intersperse with print that, I could understand. This one "VINYLBITAL SODIUM", and it chemical name (something butyl something vinylbarbituric acid) and "AS SODIUM" right beneath. I also remember that it "XTCI" logo one side, and neat little QR code, with an small inset with number on them maybe production/expiry and batch I guess and one with checkbox and signature/date marked ink. "XTCI" or whatever they from Shanghai. I remember astronomical high price for these ($800 total both), from some dude Petersham, back 2014 first one, and 2015 second. The first the vinylbital I recall it all they had they could not get nembutal it too high in demand and gone out stock and they not getting more for long time but they did more in 2015 and got second then. I have vivid memory of guy knowing what it for even if he never admit it, and his comments how it "very suitable for your needs". He did not care. Took money and delivered product. I asked guy about Tuinal and he said that last heard of it back in late 1980s. I also remember asking him Seconal and his response "Oh, that was in America they haven't made that for while and could not get that". He said most common one Nembutal, and he said it that stuff was everywhere. Of course, he is right, Nembutal is ubiquitous vets have it every hospital has it, you just can't get legally, yeah? The guy was old dude, easily in 70s.

The main thing remember is the taste. It just...so...fucking...VILE...I imagine would find hard to swallow stuff mixed with water, only 50mg of the mixed with a spoonfull of water the taste was revolting. A 200mg test dose vinylbital wanting to go to bed quickly because I knew I would not able to stay awake I'd end on the floor. Easily 15 minutes it effect. Hit hard fast. Nembutal nicer it didn't overwhelm at first you like this other shit did and took a longer. Think about 30 minute before it took hold. Funny phenobarbital didn't take much longer, I think 45 minutes after 250mg dose pheno and it quite potent.

Strange this baclofen I been taking for past 2 weeks so is allowing me access deeper memories that I forgotten. I even back when I lived in Jindabyne all silly shit I to do down there, and when I went highschool. That first day I went high school. I was not fucking 12 years old. I had like cheese sandwich and dried apricots in lunchbox. I remember being barred from school 3 days, and then 6 weeks, and then had to go back 3 day in week, then 4, then 5. Then got kicked off bus the following year over a month for throwing massive tantrum threatening the driver because he going to kick me off for week. I was swearing so much and called driver a bastard under breath. Following week kicked off. Then threw a tantrum and that was it and stopped from boarding bus until end of year.

Life memory was so funny. I remember so much now. Comical things and so silly event that could not understand now. It nonsense things mostly lot of funny things with school room object. I remember doing such silly things that result in so much discipline problem and needing to be deal with many time. But too many memory to go on and not list more for now. So I say bye for this post. I just can type no more. Go to bed in 5 minute. Too tired almost to get off chair.

 

[Flynnal]

Damn, I must have taken a double dose of Belsomra by mistake, oh and I'd taken clonazepam earlier that morning for a panic attacked, yes you guessed it caused by this stupid ear problem I have been dealing with the past 5 years or so. It won't get better, only gonna get worse.

Life is good but it also sucks so much.

 

[polymath]

To me it looks like the 1,3-propanediol sedatives such as prenderol (2,2-diethyl-1,3-propanediol) are recognized as similar to the malonic acid part of a barbiturate molecule by your GABA-A receptors, hence their similar CNS effect and the need for two alkyl substituents at the 2-carbon. Having a 1-methylbutyl substituent there, similar to secobarbital and other more potent barbiturates, could be especially good if this is the case. You would need a molecular docking simulation to see whether those molecules bind to the same part of GABA-A receptor as the barbs.